Breaking Bad News: Dynamic Molecular Mechanisms of Wound Response in Plants

Abstract

Recognition and repair of damaged tissue are an integral part of life. The failure of cells and tissues to appropriately respond to damage can lead to severe dysfunction and disease. Therefore, it is essential that we understand the molecular pathways of wound recognition and response. In this review, we aim to provide a broad overview of the molecular mechanisms underlying the fate of damaged cells and damage recognition in plants. Damaged cells release the so-called damage associated molecular patterns to warn the surrounding tissue. Local signaling through calcium (Ca²⁺), reactive oxygen species (ROS), and hormones, such as jasmonic acid, activates defense gene expression and local reinforcement of cell walls to seal off the wound and prevent evaporation and pathogen colonization. Depending on the severity of damage, Ca²⁺, ROS, and electrical signals can also spread throughout the plant to elicit a systemic defense response. Special emphasis is placed on the spatiotemporal dimension in order to obtain a mechanistic understanding of wound signaling in plants.

Full text

Frontiers in Plant Science | www.frontiersin.org 1 December 2020 | Volume 11 | Article 610445
REVIEW
published: 08 December 2020
doi: 10.3389/fpls.2020.610445
Edited by:
Massimo E. Maffei,
University of Turin, Italy
Reviewed by:
Ivan Galis,
Okayama University, Japan
Lotte Caarls,
Wageningen University and
Research, Netherlands
*Correspondence:
Simon Stael
simon.stael@psb.vib-ugent.be;
sista@psb.vib-ugent.be
Specialty section:
This article was submitted to
Plant Pathogen Interactions,
a section of the journal
Frontiers in Plant Science
Received: 25 September 2020
Accepted: 17 November 2020
Published: 08 December 2020
Citation:
Vega-Muñoz I, Duran-Flores D,
Fernández-Fernández ÁD, Heyman J,
Ritter A and Stael S (2020)
Breaking Bad News:
Dynamic Molecular Mechanisms
of Wound Response in Plants.
Front. Plant Sci. 11:610445.
doi: 10.3389/fpls.2020.610445
Breaking Bad News:
Dynamic Molecular Mechanisms of
Wound Response in Plants
IsaacVega-Muñoz
1, DaliaDuran-Flores
1, ÁlvaroDanielFernández-Fernández
2,3,
JefriHeyman
2,3, AndrésRitter
2,3 and SimonStael
2,3,4,5*
1 Laboratorio de Ecología de Plantas, CINVESTAV-Irapuato, Departamento de Ingeniería Genética, Irapuato, Mexico,
2 Department of Plant Biotechnology and Bioinformatics, Ghent University, Ghent, Belgium, 3 VIB-UGent Center for Plant
Systems Biology, Ghent, Belgium, 4 Department of Biomolecular Medicine, Ghent University, Ghent, Belgium, 5 VIB-UGent
Center for Medical Biotechnology, Ghent, Belgium
Recognition and repair of damaged tissue are an integral part of life. The failure of cells
and tissues to appropriately respond to damage can lead to severe dysfunction and
disease. Therefore, it is essential that weunderstand the molecular pathways of wound
recognition and response. In this review, weaim to provide a broad overview of the
molecular mechanisms underlying the fate of damaged cells and damage recognition in
plants. Damaged cells release the so-called damage associated molecular patterns to
warn the surrounding tissue. Local signaling through calcium (Ca2+), reactive oxygen
species (ROS), and hormones, such as jasmonic acid, activates defense gene expression
and local reinforcement of cell walls to seal off the wound and prevent evaporation and
pathogen colonization. Depending on the severity of damage, Ca2+, ROS, and electrical
signals can also spread throughout the plant to elicit a systemic defense response. Special
emphasis is placed on the spatiotemporal dimension in order to obtain a mechanistic
understanding of wound signaling in plants.
Keywords: wound response, damage, damage-associated molecular pattern, systemic signaling, herbivory,
jasmonic acid, regeneration
INTRODUCTION
Plants are especially susceptible to damage as they are unable to run away when facing danger.
Wounds can originate from harsh weather conditions (e.g., strong wind, hail, re, and frost),
physical damage (e.g., trampling), exposure to chemicals (e.g., DNA damage and toxic substances),
or biotic attack (e.g., microbes and herbivores). Damage can range in severity from single cell
death to complete removal of organs and in duration from single events to repeated injury,
for example, from chewing insects. In the lab, mechanical damage can be rather “clean” as
in cutting with a sharp razor blade, application of pin pricks, and laser-mediated wounding,
or “messy” by bruising tissue with pinches of a forceps or hemostat. Wedene here “wound”
(wounding, wound-induced, etc.) as a general term, while the type of damage that produced
the wound can be further specied, such as mechanical- or herbivore-induced damage.
In contrast to metazoans, plants do not rely on a dedicated nerve system or mobile immune
cells to sense or respond to wounds. Nevertheless, plants have evolved ecient mechanisms to

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perceive wounds and mount an appropriate defense response.
Each plant cell has the ability to transduce a signal to its
neighboring cells via damage-associated molecular patterns
(DAMPs; previously reviewed in Heil and Land, 2014). Depending
on the severity of the damage in size or location (e.g., leaf
midvein; Kiep et al., 2015; Toyota et al., 2018), the complete
plant can bealerted through a systemic signal, spreading from
local to distal tissues that comprises waves of hydraulic, electrical,
calcium (Ca2+), and reactive oxygen species (ROS) signals, and
the perception of wound-related hormones, such as jasmonic
acid (JA), ethylene, or abscisic acid (ABA). Once activated,
chemical defenses, such as the production of phytoalexins and
other secondary metabolites, or structural defenses, such as
increased production of trichomes and strengthening of cell
walls, can protect the plant from reoccurring damage (Agrawal,
1998; Maei et al., 2007b). Several aspects of the wound
response are conserved with metazoans, including the release
of certain DAMPs, Ca2+, and ROS signaling. Other traits are
plant-specic, such as the production of wound hormones and
release of wound-induced volatiles. Some responses share
similarities, such as the production of oxylipins (JA in plants
and prostaglandins or leukotrienes in metazoans) and activation
of membrane localized receptors by DAMPs and downstream
phosphorylation cascades to activate defense gene expression
(previously reviewed in León etal., 2001; Maei etal., 2007a;
Heil and Land, 2014; Savatin et al., 2014).
e ability to sense and appropriately respond to wounds
is crucial for survival. On the one hand, a defective or
overwhelmed defense response leads to increased plant mortality
(Agrawal, 1998), especially what concerns the replenishment
of stem cells and regeneration of organs in the root and
shoot apical meristems and cambium (Sena et al., 2009;
Heyman etal., 2013; Efroni etal., 2016). On the other hand,
mechanisms are in place to prevent plants from overreacting
to wounds and, when compromised, can lead to uncontrolled
spread of cell death (Cui et al., 2013) or hypersensitivity to
wounding (Zhang et al., 2019). Wound healing and defense
responses can prevent excessive water loss (Consales et al.,
2012; Cui etal., 2013; Becerra-Moreno etal., 2015), attenuate
pathogen infection (Tarr, 1972; Lulai and Corsini, 1998; Zhou
et al., 2020), and deter herbivores (previously reviewed in
Erb and Reymond, 2019).
In nature, wounds are likely pervasive even when not visible
to the naked eye and provide easy access sites for some pathogens,
especially wound parasites such as wood rot and canker fungi
(previously reviewed in Tarr, 1972). Pathogen colonization is
prevented by wound healing processes, such as production of
cork, callus, resin, or gum, and relies on rapid sealing of wounds
(Lulai and Corsini, 1998). Furthermore, the immune system is
activated in response to wounding (Savatin et al., 2014; Zhou
et al., 2020). erefore, wound-induced resistance can inhibit
pathogen growth, for example, in the local resistance to Botrytis
cinerea (Chassot et al., 2008; García et al., 2015), although it
likely depends on environmental circumstances, such as high
humidity (L’Haridon etal., 2011) and the natural genetic variation
of the host plant (Coolen et al., 2019). Furthermore, eective
colonization of the wound depends on the timing of contact
with the pathogen (present before wounding or only aer) and
degree of wounding (Lulai and Corsini, 1998; Chassot et al.,
2008). erefore, pathogen entry via wounds merits further
investigation and should beevaluated in a case-by-case scenario.
Both microbes and invertebrate herbivores will attempt to subvert
wound-induced defense responses. Interaction with chewing or
sucking insects is further complicated as both insects and insect-
borne microbes produce elicitors and suppressors of plant
defense, in which JA signaling is oen the target (previously
reviewed in Basu et al., 2018). Due to the co-evolution of
plants and pests, it is to beexpected that every wound response
is a potential target for suppression by pathogens and herbivores.
erefore, interactions of wounds with biotic challenges pose
interesting cases, where wound responses can be enhanced or
subverted, and some examples will be highlighted throughout
this review.
Studies of wound response in plants present a long tradition
of research. Whereas the rst studies were mainly descriptive
(Bloch, 1941; Lipetz, 1970), in the last decades, molecular
mechanisms are increasingly becoming clear (León etal., 2001;
Maei et al., 2007a; Savatin et al., 2014). For information on
wound healing and mitigation of damage in post-harvest
processes in vegetables and fruit, werefer to specic literature
(Cisneros-Zevallos etal., 2014; Lulai etal., 2016; Saltveit, 2016;
Iakimova and Woltering, 2018; Hussein etal., 2020). is review
provides a broad overview of the recent developments in
molecular mechanisms with a focus on spatiotemporal dynamics
in order to gain mechanistic understanding and to address
open questions in the eld of wound response in plants.
LOCAL VS. SYSTEMIC WOUND
SIGNALING
Wound signaling can bedivided in a local and systemic response.
Cells at the site of injury can be completely destroyed or
bruised (Iakimova and Woltering, 2018) and, at least in leaves,
cell death ensues at the timescale of hours to days in 2–3
cell layers away from the site of injury (Cui et al., 2013;
Iakimova and Woltering, 2018). Together with the local deposition
of lignin, callose, and phenolics, cell death likely functions as
a physical barrier to seal-o the injury and protects the adjacent
intact tissue (Savatin et al., 2014; Iakimova and Woltering,
2018). DAMPs released from wounds signal the surrounding
intact cells via Ca2+, ROS, phosphorylation, and electrical
signaling to mount defense gene expression. Most likely, direct
physical responses, such as changes in mechanical forces and
cell pressure surrounding the wound, play a pronounced signaling
role, although these are largely unknown (Routier-Kierzkowska
etal., 2012; Hoermayer etal., 2020). In parallel and depending
on the severity of damage, systemic signals are propagated
from the wound site to the rest of the plant, comprising leaf-
to-leaf, root-to-root, leaf-to-root, and root-to-leaf signaling.
Local and systemic responses are inherently linked at least
through Ca2+, ROS, and electrical signaling, and, where
information is available, links will be highlighted throughout
the review.

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The Ins and Outs of DAMPs Generation
and Recognition
Plants have evolved mechanisms that allow them to respond
quickly to wounding and to distinguish the self from the
non-self (Heil and Land, 2014; Savatin et al., 2014). Plant
innate immunity relies on cell surface receptors that allows
activation of defense responses via the recognition of conserved
exogenous pathogen-derived (non-self) or endogenous (self)
danger signals by transmembrane pattern-recognition receptors
(PRRs). ese conserved danger signals are also termed as
pathogen-associated molecular patterns [PAMPs; also named
microbe-associated molecular patterns (MAMPS) in the literature]
for the non-self-signals and DAMPs for the self-signals (Choi
and Klessig, 2016). In this review, wewill discuss recent progress
on several prominent DAMPs and their links to wound response,
while for an extensive overview of DAMPs, we refer to recent
excellent reviews (Choi and Klessig, 2016; Duran-Flores and
Heil, 2016; Gust et al., 2017; Hou et al., 2019).
Primary/Constitutive and Secondary/Inducible
DAMPs
Wounding either by mechanical damage, herbivores, or microbial
infections results in disruption of plant tissue and subsequent
release of intracellular molecules and cell wall-associated
molecules into the apoplastic space (Mithöfer and Boland,
2012; Choi and Klessig, 2016; Duran-Flores and Heil, 2016;
Figure 1A). Herbivores destroy plant tissues during feeding
and/or by chemical modication while microbial infection-
induced plant damage is oen caused by deleterious activities
of microbial hydrolytic enzymes or toxins (D’Ovidio et al.,
2004; Horbach etal., 2011). Molecules released passively upon
host damage conform to the denition of “classical” or primary
DAMPs (Matzinger, 1994), which are molecules that have a
physiological role during homeostasis but indicate damage
when they appear outside the cell. Examples are ATP, cell
wall fragments occasioned by wounding or pathogen derived
cell wall degrading enzymes, or fragmented DNA caused by
pathogen DNases (Claverie etal., 2018; Hadwiger and Tanaka,
2018; Huang etal., 2019; Jewell and Tanaka, 2019). Location
is important, as these DAMPs are invisible to the immune
system during homeostasis and are passively exposed to the
extracellular environment, thereby acting as early and general
activators of the plant immune system (Vénéreau etal., 2015;
Choi and Klessig, 2016). us, primary DAMPs are not linked
to biosynthesis or secretion from undamaged cells. e secondary
or inducible DAMPs are endogenous molecules actively produced
or modied during cell death and function exclusively as
signals. ey can be secreted passively or actively upon
wounding or microbial infection by either damaged or
undamaged cells and include, for example, small signaling
peptides (Gust et al., 2017; Li et al., 2020). Details about the
temporal activation of the signaling molecules and hormones
upon perception of DAMPs mentioned in the text can
be retrieved in Table 1.
A
B
C
FIGURE1 | Overview of local damage at early time-points following signaling processes. (A) Damaged cells suffer fragmentation of their cellular components,
releasing a mixture of different damage-associated molecular patterms [DAMPs (DAMP cocktail)] to the surrounding environment. Reactive oxygen species (ROS)
and Ca2+ contribute to plasmodesmata blockage and later accumulation of callose. (B) DAMPs are perceived by specic receptors, generally receptors like kinases
in the plasma membrane. DAMP sensing is normally accompanied by hallmark signal transduction events, such as MAPK phosphorylation cascades, that result in
transcription factor phosphorylation and modulation of defense gene expression. (C) Parallel to local perception by receptors, certain signals such as Ca2+, ROS,
and glutamate can travel from the wound site in a distance-dependent gradient along the apoplast. GLR and CNGC channels can beactivated by DAMPS such as
glutamate and Pep1. Intracellular Ca2+ serves as a component to activate calcium-dependent protein kinases (CDPK) and calmodulin-like proteins (CML), which
contribute to transcriptional responses. Together, oxygen radicals are generated locally in the extracellular space and transformed to more stable ROS species by
RBOHs, thus adjusting the ROS wave signal.

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TABLE1 | Timing and localization of DAMP release/generation and wound responses in plants.
DAMP Receptor Release/generation Localization Response Source Response time Plant species References
Ogs WAK1/2
< 4h
(Polygalacturonase;
Bergey etal., 1999)
-
Ca2+ Ex 2min Tobacco Chandra and Low,
1997
ROS Ex 2h Tobacco Bellincampi etal., 2000
ROS Ex 15min Arabidopsis Galletti etal., 2008
MAPK Ex 3min Arabidopsis Denoux etal., 2008
NO Ex/in vivo 30min Arabidopsis Rasul etal., 2012
Callose Ex 18h Arabidopsis Denoux etal., 2008
eATP P2K1 < 1min
(Song etal., 2006)Extracellular
Ca2+ Ex 30–40s Arabidopsis Tanaka etal., 2010
Ca2+ Ex/in vivo 1–2min Arabidopsis Demidchik etal., 2009
ROS Ex/in vivo 15s Arabidopsis Demidchik etal., 2009
ROS Ex/in vivo 5min Medicago Kim etal., 2006
JA Ex/in vivo 24h Tomato Wu etal., 2012
Et Ex/in vivo 24h Tomato Wu etal., 2012
NAD(P)+ LecRK-1.8/VI.2 < 20min
(Zhang and Mou, 2009)Extracellular
SA Ex 4h Arabidopsis Wang etal., 2017
PR genes Ex/in vivo 24h Arabidopsis Zhang and Mou, 2009
SA Ex - Arabidopsis Zhang and Mou, 2009
HMGB3 - 24h
(Choi etal., 2016)Apoplast MAPK Ex/in vivo 15min Arabidopsis Choi etal., 2016
Callose Ex/in vivo 15h Arabidopsis Choi etal., 2016
DNA - - -
Ca2+ Ex 30min Maize Barbero etal., 2016
Ca2+ Ex 30min Lima Bean Barbero etal., 2016
ROS Ex 2h Common Bean Duran-Flores and Heil,
2018
MAPK Ex 30min Common Bean Duran-Flores and Heil,
2018
Systemin SYR1/2
3–4h
(mRNA; McGurl etal., 1992)Intracellular
Ca2+ Ex 2min Tomato Moyen etal., 1998
ROS Ex/in vivo 4h Tomato Orozco-Cardenas and
Ryan, 1999
MAPK Ex/in vivo 2min Tomato Stratmann and Ryan,
1997
18h
(prosystemin;
Narváez-Vásquez and Ryan,
2004)
Phloem
Et Ex/in vivo 30min Tomato O’Donnell etal., 1996
JA Ex/in vivo 15min Tomato Narváez-Vásquez etal.,
1999
PI in vivo 1h Tomato Howe etal., 2000
Inceptin INR - -
JA Ex/in vivo 30min Cowpea Schmelz etal., 2007
Et Ex/in vivo 120min Cowpea Schmelz etal., 2007
SA Ex/in vivo 240min Cowpea Schmelz etal., 2007
Glutamate GLR < 1min
(Toyota etal., 2018)Vasculature
Ca2+ in vivo 1min Arabidopsis Toyota etal., 2018
Ca2+ Ex 1min Arabidopsis Shao etal., 2020
SA Ex 6h Arabidopsis Goto etal., 2020
JA Ex 7h Arabidopsis Goto etal., 2020
AtPep1 AtPEPR1/2 0.5–5min
(Hander etal., 2019)Intracellular
Ca2+ Ex 40s Arabidopsis Ranf etal., 2011
MAPK Ex 2min Arabidopsis Ranf etal., 2011
ROS Ex 4min Arabidopsis Flury etal., 2013
AtPep3 AtPEPR1
24h
(Yamada etal., 2016;
Engelsdorf etal., 2018)
Extracellular
ROS Ex 2h Rice cells Shinya etal., 2018
MAPK Ex 15min Rice cells Shinya etal., 2018
JA Ex 3h Rice cells Shinya etal., 2018
JA in vivo 4h Arabidopsis Klauser etal., 2015
Ex, exogenous application; ROS, reactive oxygen species; MAPK, mitogen-activated protein kinase; NO, nitric oxide; JA, jasmonic acid; SA, salicylic acid; Et, ethylene, PR, pathogenesis related; and PI, protease inhibitors.

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Oligogalacturonides
Cell wall integrity is crucial for plant growth and development
as well as in preventing wounding and pathogen attack
(Bellincampi et al., 2014). Perception of an altered cell wall
integrity is proposed to be a key event during wounding
(Nühse, 2012; Wolf et al., 2012; Wolf, 2017), although
experimental evidence is lacking so far. Oligogalacturonides
(OGs) are released from the plant cell walls from the
fragmentation of homogalacturonan, the main component of
pectin, either by endogenous wound-induced polygalacturonases
or during infection by microbial polygalacturonases (Savatin
etal., 2014). OGs are relatively immobile in the plant vascular
system and may act as a local signal; however, because
polygalacturonase activity is induced systemically in response
to wounding, OGs may amplify responses in undamaged leaves
(Tabl e 1 ; Bergey et al., 1999). e size of OG fragments is
a major factor dictating their elicitor activity, being OGs with
a degree of polymerization between 10 and 15 the most active
while shorter oligomers are inactive. OG-induced defense
responses include production of ROS (Bellincampi etal., 2000),
mitogen-activated protein kinase (MAPK) activation (Denoux
et al., 2008), nitric oxide (NO; Rasul et al., 2012), and
upregulation of phytoalexins and glucanase (Davis and
Hahlbrock, 1987), chitinase (Broekaert and Peumans, 1988),
and callose (Denoux et al., 2008; Galletti et al., 2008). In
tomato, OGs induce the accumulation of a protease inhibitor,
which is eective against insect herbivores (Moloshok et al.,
1992; Ryan and Jagendorf, 1995). e Arabidopsis wall-associated
kinase 1 (WAK1) has been described as an OG receptor. In
vitro studies have demonstrated that WAK1 binds to
polygalacturonic acid, pectins, and specically to OGs with
a degree of polymerization over nine moieties (Decreux and
Messiaen, 2005; Cabrera et al., 2008; Brutus et al., 2010).
Furthermore, gene expression studies indicate that WAK1 is
upregulated by wounding and exogenous application of OGs
(Wagner and Kohorn, 2001; Denoux etal., 2008; Ferrari etal.,
2013). Alterations in the expression of WAK1 and of its
interactors disturb the local response to wounding (Gramegna
et al., 2016; De Lorenzo et al., 2018). Hyperaccumulation of
OGs may aect growth of the whole plant, eventually leading
to cell death (Benedetti et al., 2015), suggesting that OGs
play a role in the growth-defense trade-o (Huot etal., 2014).
Hence, plants limit the hyperaccumulation of OGs by a battery
of at least four Arabidopsis enzymes belonging to the family
of the so-called berberine-bridge enzyme (BBE-like) proteins
(Daniel et al., 2017). BBE-like proteins specically oxidize
OGs and produce oligosaccharides that reduce the ability to
induce expression of defense genes, ROS burst, and deposition
of callose (Benedetti et al., 2018). Similarly, cellodextrines,
degradation products of cellulose, trigger a signaling cascade
during immunity, and oxidation by other BBE-like proteins
impairs elicitor activity (Locci et al., 2019). Recently, an
application of OGs accelerated mechanical wound healing in
tomato fruit via elicitation of callose deposition, defense gene
expression, lignin biosynthesis, and phenylalanine ammonia-
lyase activity around the wound in a Ca2+ signaling-dependent
manner (Lu et al., 2021).
Extracellular ATP, NAD+, and NADP+
Adenosine-5-triphosphate (ATP) represents the universal energy
source for metabolic processes. During wounding, ATP is
released immediately from the cytoplasm to the outside of
the cell (Table 1). is extracellular ATP (eATP) is recognized
as a DAMP and has been reported to activate defense responses
in fungi, mammals, and plants (Medina-Castellanos etal., 2014;
Tripathi and Tanaka, 2018; Roux and Clark, 2019). Concentrations
of approximately 40 uM eATP have been measured in the
extracellular uid present at wound sites within 3min following
damage to Arabidopsis leaves, which are sucient to initiate
an immune response (Song et al., 2006). In mammals, eATP
is recognized by plasma membrane-localized P2-type purinergic
receptors. In Arabidopsis, eATP, as a DAMP, is sensed by the
L-type lectin receptor kinases P2K1 (also known as does not
respond to nucleotides 1 or DORN1) and P2K2 at concentrations
well below 40 uM (Choi J. et al., 2014; Pham et al., 2020).
Transcriptional studies of a p2k1 mutant in the absence of
stimuli revealed only 21 dierentially expressed genes compared
to the wild type. Such a small number could indicate that
P2K1-mediated eATP signaling does not play a major role in
growth and development under homeostasis (Jewell and Tanaka,
2019). Approximately 60% of the genes induced by eATP are
also induced by wounding, indicating that eATP plays an
important role in response to wounding (Choi J. etal., 2014).
Furthermore, physical damage in plants that overexpress P2K1
enhanced upregulation of wound-induced gene expression, while
this expression is notably reduced in the p2k1-3 mutant (Choi
J. etal., 2014). Early eATP induced responses include membrane
depolarization, Ca2+ inux, ROS formation, malondialdehyde
production, enzymatic activity (catalase and polyphenol oxidase),
JA, and ethylene biosynthesis (Kim et al., 2006; Tanaka et al.,
2014; Tripathi et al., 2018; Wang Q.-W. et al., 2019). eATP
treatment of wounded tissue resembles a JA-dependent defense
response, resulting in the secretion of extraoral nectar in
lima bean to attract predators of herbivores (Heil etal., 2012).
Induced immunity by eATP has been reported at the phenotypic
level in response to bacteria (Chivasa etal., 2009; Chen et al.,
2017), necrotrophic fungi (Tripathi etal., 2018), and herbivores
(Heil etal., 2012). ATP receptors, p2k1-3, p2k2 single mutant,
and p2k1p2k2 double mutants, are more susceptible to bacterial
infection compared to the wild type, whereas P2K2 complemented
lines showed no dierence to the wild type and ectopically
expressed P2K2 showed elevated resistance to bacterial infection
(Pham etal., 2020). Saliva from Helicoverpa zea larvae degrades
eATP from tomato leaves via multiple ATPases. e ATPases
also suppress wound-induced expression of glandular trichomes
in newly forming leaves, thus acting as a herbivore eector
suppresses eATP induced wound response (Wu et al., 2012).
Similarly, mechanical stress can be coupled to the release of
extracellular ATP. In fact, it plays an important role in the
root avoidance response, where sensing mechanical stimulation
elicited by contacting an object triggers root growth, allowing
it to avoid and overcome physical obstacles. Exogenously applied
ATP changes the sensitivity of the root tip to the growth-
regulating plant hormone auxin and reduces shootward auxin
transport (Tanaka et al., 2010). Plants respond to eATP in a

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dose-dependent manner. Constitutive levels of eATP appear
to be essential, as depletion can trigger cell death (Chivasa
et al., 2005), while low (30 μM) or moderate (150 μM) doses
of eATP can stimulate or suppress cell elongation, respectively
(Clark et al., 2010). High eATP doses (>500 μM) reduce cell
viability and can trigger programed cell death (Sun etal., 2012;
Deng et al., 2015). While there is no direct evidence that
eATP alone aects plant growth/regeneration aer wounding,
data suggest that a combination of several cues like DAMPS,
PAMPS, ion/osmolyte concentrations, or mechanical stresses
trigger a defense and regeneration response (Marhavý etal., 2019;
Shanmukhan et al., 2020; Zhou et al., 2020).
NAD+ and NADP+, as di-nucleotides and similarly to ATP
acting as a classical cofactor, can bereleased to the environment
aer wounding, through membrane leakage or active processes
such as exocytosis in animal model species (Haag etal., 2007).
In Arabidopsis, an application of exogenous NAD+ (eNAD+)
and eNADP+ is sucient to induce salicylic acid (SA)
accumulation, expression of pathogenesis-related (PR) genes,
and resistance to pathogens (Zhang and Mou, 2009; Wan g
et al., 2017). A lectin receptor kinase, LecRK-I.8, was found
to be partially responsible for eNAD+ perception (Wang et al.,
2017), while LecRK-VI.2 has been proposed as a receptor of
both eNAD+ and eNADP+ (Wang C. etal., 2019). Transcriptome
analyses suggest that eNAD+ signaling upregulates genes involved
in PAMP triggered immunity and SA pathways but suppresses
genes of the JA and ethylene pathways, which are more related
to wounding (Wang etal., 2017). However, eNAD+ and eNADP+
leak into the extracellular space during mechanical wounding
and pathogen-induced hypersensitive response in concentrations
high enough to induce the latter responses (Ta bl e 1), raising
the possibility that they act as DAMPs (Zhang and Mou, 2009;
Wang C. et al., 2019).
High Mobility Group Box Proteins
High mobility group box (HMGB) proteins are highly conserved
chromatin-architecture regulators found in all eukaryotes,
including plants. Mammalian HMGB1 was one of the rst
DAMPs to be identied and is extensively characterized and
considered a primary DAMP (Choi and Klessig, 2016). Briey,
human HMGB1 binds in the nucleus to DNA, facilitating
nucleosome formation and transcription factor binding (omas
and Travers, 2001; Lotze and Tracey, 2005). Upon its release
outside the cell, it can be recognized by various cell surface
receptors (Heil and Vega-Muñoz, 2019). In metazoans, HMGB1
facilitates tissue repair and healing by promoting the switch
of macrophages to a tissue-healing phenotype (Bianchi et al.,
2017). Based on their nuclear location and domain structure,
plant HMGB-type proteins might function in a similar way
to mammalian HMGB1. e presence of extracellular AtHMGB3
raised the possibility that, similar to the classical role of HMGB1
as mammalian DAMP, it serves in a similar way in plants
(Choi et al., 2016). Notably, AtHMGB2/3/4 are present in the
cytoplasm as well as in the nucleus. Cytoplasmic functions
for these proteins have not yet been reported; however, it is
theorized that the cytosolic subpopulation might have easy
access to the apoplast aer wounding in comparison to the
ones found in the nucleus (Pedersen et al., 2010; Choi and
Klessig, 2016). To our knowledge, there is no evidence that
AtHMGB3 is secreted into the apoplast, so extracellular
AtHMGB3 is most likely the result of cell membrane rupture.
In fact, tissue damage during Botrytis cinerea infection causes
the release of AtHMGB3 to the apoplast aer 24h of inoculation,
whereas a control protein, histone H3, only appears in the
total leaf and nuclear extracts at that timepoint, suggesting
that AtHMGB3 is released early during necrosis (Table 1; Choi
etal., 2016). Exogenous application of AtHMGB3 induces innate
immune responses like MAPK activation, defense gene expression,
callose deposition, and enhanced resistance to pathogen infection
(Choi et al., 2016).
DNA
Plant immunity can be activated upon the sensing of DNA.
Cell death during pathogen infection or abiotic stresses leads
to DNA fragmentation (Ryerson and Heath, 1996; Kuthanova
etal., 2008). Fragmented DNA can beexposed to the apoplast
and function as a DAMP. Several recent studies have found
evidence that the host-derived fragmented DNA (<700 bp)
triggers early plant defense responses, such as membrane
depolarization, Ca2+ inux, ROS production, and MAPK
activation, and eventually induces changes in CpG methylation,
and increases plant resistance to pathogen infections (Wen
etal., 2009; Barbero et al., 2016; Duran-Flores and Heil, 2018;
Vega-Muñoz et al., 2018). Intriguingly, the ability of non-self-
derived DNA to trigger an immune response is lower or
undetectable than the ones induced by self-derived DNA
(Duran-Flores and Heil, 2018), suggesting a species-specic
perception mechanism that discriminates self-derived DNA
from non-self DNA. To date, no DNA receptor has been
identied in plant cells, and none of the receptors that are
known from mammals discriminate between self and non-self
DNA (Heil and Vega-Muñoz, 2019). Extracellular DNA present
on plant root tips is required for defense against a necrotrophic
fungus (Wen et al., 2009), and it was recently reported that
secreted DNases by a fungal pathogen (Cochliobolus
heterostrophus) and a herbivore (Laodelphax striatellus) serve
as eectors that suppress DNA-dependent plant immunity,
reinforcing the biological relevance of DNA as a DAMP in
plants (Huang et al., 2019). Importantly, to the best of our
knowledge, there is no evidence for wound-induced DNA
release to the apoplast in plants. However, based on evidence
of DNA release in mammalian studies (Marichal et al., 2011;
Pottecher et al., 2019; Gong et al., 2020), it is anticipated to
besimilarly present in plants, but requires further investigation.
Links between the DNA damage response (DDR), cell cycle,
programed cell death, and immunity have emerged in recent
years (Song et al., 2011; Yan et al., 2013; Hu et al., 2016;
Johnson et al., 2018). Depending on the cell type and the
severity of the DNA damage, dierent cellular responses are
triggered. In mammals, mild DNA damage leads to cell-cycle
arrest, whereas severe and irreparable damage leads to senescence
or cell death programs (Surova and Zhivotovsky, 2013). In
plants, the presence of damage-inducing agents or defective
DNA repair leads to aberrant organogenesis and development,

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as well as loss of biomass (Hu et al., 2016). In addition, other
reports link DDR to the activation of the plant immune system.
Pathogen infection triggers the production of SA, which in
turn induces DNA damage that can be sensed by DNA repair
mechanisms to the site of DNA damage for repair or activation
of defense gene expression (Yan et al., 2013). Suppressor of
gamma response 1 (SOG1) is a transcription factor of the
NAC family and is a central regulator of the plant DDR
(Yoshiyama et al., 2009). DDR has been reported to play an
essential role for plants to cope with various environmental
stresses (Yan etal., 2013; Hong etal., 2017; Ogita et al., 2018).
sog1-1 mutants are decient in DDR and immune response,
while SOG1 overexpression in the presence of zeocin, a double-
strand DNA break agent, enhances DDR, the expression of
genes involved in chitin response, and fungal resistance
(Yoshiyama etal., 2020). Ethylene response factor 115 (ERF115)
is a transcription factor that is upregulated in meristematic
cells that are positioned adjacent to dead ones in the root
tip. Severe stress conditions may cause irreparable DNA damage
resulting in cell death, followed by the induction of regeneration
in an ERF115-dependent manner (Heyman etal., 2016, 2018).
Besides SA, specic agents that cause DNA alterations (e.g.,
DNA helical distortion, intercalation, base substitutions,
methylation, etc.) enhance defense gene expression. DNA damage
and resulting chromatin structural changes may be a central
mechanism in initiating defense gene transcription during
nonhost resistance (Hadwiger and Tanaka, 2018). Links between
DNA damage, immunity, and regeneration have been emerging
in the last years, yet, it remains unclear how DNA is sensed
as no formal DNA receptors have been reported.
Systemin and Other Small Signaling Peptides
Small signaling peptides can be generated as the product of
two activities: by transcriptional responses inducing small open
reading frames coding for small peptides or by proteolytic
processing of precursor proteins (Tavormina et al., 2015; Hou
et al., 2019). Proteolytic cleavage generates peptides that are
able to alarm surrounding tissues about the imminent stress
when perceived via plasma membrane associated receptor-like
kinases (Wang and Irving, 2011; Stührwohldt and Schaller,
2019). Although experimental evidence has accumulated over the
last years, the functions, receptors, mode of actions, and proteases
that liberate the peptides from their precursors are still largely
unexplored (Tavormina et al., 2015; Schardon et al., 2016;
Hander et al., 2019; Chen et al., 2020).
Systemin was the rst reported extracellular peptide that
induces defense signaling in plants (Pearce et al., 1991). From
its precursor, prosystemin, mature systemin (18 amino acids
in length) is partially processed by the cysteine protease
phytaspase and released into the apoplast during mechanical
damage (Beloshistov et al., 2018). Phytaspase might get access
to intracellular prosystemin via cellular disruption or via active
delocalization upon programed cell death (Chichkova et al.,
2010; Beloshistov et al., 2018). Prosystemin expression is low
in unwounded leaves and increases several fold, peaking around
4 h aer wounding (McGurl et al., 1992). Prosystemin
accumulates mainly in the cytosol and nucleus of phloem
parenchyma cells (Narváez-Vásquez and Ryan, 2004). Systemin
specically binds its receptors Systemin receptor 1 and 2 (SYR1
and SYR2), which is sucient to induce the typical response
including a ROS burst, ethylene production, and the expression
of two wound induced proteinase inhibitors in tomato (Wang
etal., 2018). Functionally related peptides are the hydroxyproline-
rich glycopeptide systemins. Repetition of these peptides found
in the polypeptide precursor proHypSys is thought to magnify
the intensity of the wound response once processed (Pearce,
2011). ese genes encode dierent peptides for tobacco, petunia,
tomato, and sweet potato but have in common that they are
transcriptionally responsive to wounding and/or JA, and above
all, they induce similar responses as systemin (Pearce et al.,
2001, 2007; Ryan and Pearce, 2003; Ren and Lu, 2006; Chen
et al., 2008). Systemin has only been identied in Solanaceae
species (Pearce et al., 1991). However, peptides similar to
systemin have been identied in other plant species, such as
HypSys, Peps, GmSubPep, GmPep914, GmPep690, and PIPs,
that act as DAMPs, eliciting high levels of proteinase inhibitors,
JA, and release of volatiles within minutes of exogenous peptide
application (Albert, 2013; Huaker etal., 2013; Hou etal., 2019).
Protein elicitor peptide 1 (Pep1) was extracted from
Arabidopsis thaliana lysates (Huaker et al., 2006) and is the
founding member of a gene family in Arabidopsis of eight
with various expression patterns under normal and biotic or
abiotic stress conditions (Huaker and Ryan, 2007; Bartels
et al., 2013; Bartels and Boller, 2015). Peps are encoded in
the C-terminus of their precursors, PROPEPs, which are found
in both monocots and dicots (Huaker etal., 2013; Lori etal.,
2015) and play multiple roles in defenses to pathogens,
herbivores, and abiotic stresses (Ross et al., 2014; Klauser
et al., 2015; Yamada et al., 2016; Engelsdorf et al., 2018; Lee
et al., 2018; Nakaminami et al., 2018; Zheng et al., 2018; Jing
et al., 2020; Zhang and Gleason, 2020). Ca2+ release in
mechanically damaged cells activates the cysteine protease
metacaspase4 (MC4) to cleave Pep1 from its precursor PROPEP1
within 5 min aer wounding (Hander etal., 2019; Zhu etal.,
2020). Metacaspases are evolutionary conserved proteases with
nine members in the Arabidopsis gene family (Klemenčič and
Funk, 2018; Minina etal., 2020) of which various metacaspases
can cleave dierent PROPEPs (Hander etal., 2019; Shen etal.,
2019). Cleavage of PROPEP1 seems to beessential for release
of Pep1 from the tonoplast (Bartels etal., 2013; Hander etal.,
2019). However, cleavage might not be required for others
as unprocessed PROPEP3 was found to accumulate in the
apoplast within 24h aer Pep treatment, pathogen challenge,
and in response to cell wall damage (Yamada et al., 2016;
Engelsdorf etal., 2018; Table1). Downstream, Peps are perceived
by the receptor-like kinases PEP receptor 1 and 2 (PEPR1
and PEPR2; Yamaguchi et al., 2006, 2010; Krol et al., 2010;
Tang et al., 2015). Fluorescently labeled Pep1 travels locally
in root tissue within a minute aer external application and
undergoes endocytosis when bound to PEPR1/2 (Ortiz-Morea
et al., 2016). Recently, the Ca2+-permeable channel cyclic
nucleotide gated channel 19 (CNGC19) was proposed to act
downstream of Pep perception in generating Ca2+ uxes during
herbivory (Meena et al., 2019).

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Peptidome approaches to identify native peptides directly
from protein extracts allowed the identication of novel peptide
DAMPs. A tomato pathogenesis related 1b (PR-1b) derived
peptide identied from wounded and JA-treated plants forms
the basis of a conserved family of CAPE peptides named aer
PR1b, which belongs to the cysteine-rich secretory proteins,
antigen 5, and pathogenesis-related 1 proteins (CAP) superfamily
(Chen et al., 2014; Chien et al., 2015). CAPE peptides operate
during herbivore attack by activation of stress responsive genes,
including proteinase inhibitors, and treatment with exogenous
CAPE retards the growth of herbivores and confers resistance
to Pseudomonas syringae pv. tomato DC3000in tomato (Chen
et al., 2014). In a recent peptidome approach, two interesting
peptides were identied from developing Arabidopsis tracheary
element cells (Escamez et al., 2019). Kratos and Bia (named
aer the children of the Styx river separating the worlds of
the living and the dead in Greek mythology) decrease and
enhance cell death during the incubation of leaf discs on the
peptides, respectively (Escamez et al., 2019). While this hints
at a novel role for Kratos in reducing wound-induced cell
death, further investigation is needed.
Interactions Between DAMPs, HAMPs, and
PAMPs
Herbivore associated molecular patterns (HAMPs) and pathogen
associated molecular patterns (PAMPs) allow plants to perceive
an attack from herbivores and pathogens, respectively, and
interactions with responses to DAMPs have been described
in the literature. Herbivory, for example, feeding by Spodoptera
sp. caterpillars on Lima bean (Phaseolus lunatus) or Medicago
truncatula or the application of HAMPs into mechanically
inicted wounds elicits conserved downstream signal
amplication cascades (Duran-Flores and Heil, 2016). ese
cascades involve membrane depolarization, Ca2+ inuxes, ROS
formation, and the release of green leaf-volatiles (GLVs) within
minutes, followed by MAPK phosphorylation and octadecanoid
signaling cascades in the rst hour following stress perception
(Maei et al., 2004, 2006; Arimura et al., 2008; Fürstenberg-
Hägg et al., 2013; Schmelz, 2015). None of these responses
are specic for a single type of herbivore or HAMP. Furthermore,
in all cases of HAMP application, the leaves are mechanically
damaged; hence the presence of DAMPs is unavoidable and
the specic eects of DAMPs and HAMPs are dicult to
bedistinguished (Huaker etal., 2013). Albeit a more articial
system, application of elicitors to suspension cell culture
circumvents the unintended consequences of wounding and
to disconnect the application of elicitors from the wound
response (Shinya et al., 2018). Simultaneous application of
Oryza sativa Pep3 and oral secretions from Mythimna loreyi
has an additive eect on the production of ROS and MAPK
activity and a synergistic eect on defense metabolite
accumulation in comparison to separate application. is suggests
that while DAMPs and HAMPs alone can trigger a defense
response, perceiving both is critical for the strength of the
induced plant defenses (Shinya et al., 2018).
A recent study provides a strong evidence for the positive
interaction between wounding and PAMP recognition.
Whereas applications of PAMPs do not or only weakly trigger
immune-related gene expression in the Arabidopsis root, the
co-incidence of accidental- or laser-induced damage highly
amplies this response as early as 4h aer wounding (Zhou
et al., 2020). A localized and specic response is produced,
as mostly close cells from underlying tissues, opposed to
surrounding cells of the same tissue, respond strongly to the
combination of PAMPs and damage. Wounding locally gates
the expression of PAMP receptor kinases, and, thereby, immune
responses to both benecial or detrimental bacteria in roots.
Co-application of the typical PAMP g22 with DAMPS,
including Pep1, eATP, cellobiose, OGs, or a cocktail thereof,
however, does not induce immune-related gene expression
to the extent as mechanical damage, suggesting that damage
perception is more complex and likely involves other cues
such as mechanical stress (Zhou et al., 2020).
Inceptin peptide is generated when cowpea (Vigna unguiculata)
leaves are consumed by armyworm (Spodoptera frugiperda)
larvae. Inceptin is produced by proteolysis of the cowpea
chloroplastic ATP synthase γ-subunit (cATPC protein) in the
insect gut and is then regurgitated back to the wound site
(Schmelz et al., 2006). Inceptin stands in an intermediate
position between HAMP and DAMP as conceptually speaking
it is very similar, for example, to systemin, as it originates
from a plant protein yet is dierent in the way that wounding
alone does not trigger processing, and it requires a biotic
attacker to process the peptide in order to trigger wound
response (Duran-Flores and Heil, 2016). Inceptin is a disulde-
bridged peptide containing 11 amino acids. Exogenous treatment
of cowpea with inceptin promotes the production of ethylene,
SA and JA, and defense metabolite cinnamic acid, upregulates
transcription of cowpea protease inhibitor, and enhances cowpea
resistance to herbivory. Sequence alignments of cATPC proteins
from multiple plant species demonstrate a high degree of
conservation in the amino acid sequence related to the predicted
inceptin peptides. However, inceptins are active elicitors of
defense responses only in some Fabaceae (Schmelz et al., 2007;
Li et al., 2020), suggesting that inceptin perception is a recent
evolutionary event in plants. Recently, a leucine-rich repeat
receptor-like kinase was found for inceptin in cowpea, being
the rst HAMP receptor to be reported and expanding the
current knowledge of surface immune recognition to include
herbivory (Steinbrenner et al., 2019).
Keeping Your Friends Close: Local
Damage Signaling by Ca2+, ROS, and
Phosphorylation
Local wound signaling is dened as occurring typically a few
cell layers away but, in terms of electrical signaling, can also
relate to the whole wounded leaf (but not systemic leaves; see
next section) and will depend on the severity of the wound.
Receptor kinases, as mentioned in the previous sections, likely
play an important role in perceiving a cocktail of DAMPs
that is released in the immediate surrounding of wounds
(Figure 1B). Ca2+ is a conserved second messenger involved
in the initial signaling cascades of multiple physiological actions

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and in response to biotic and abiotic stresses (Kudla etal., 2010).
Across scales of wounding, from single cell laser-mediated
damage in roots to pin pricks and herbivory in leaves, cytosolic
Ca2+ levels are the highest and remain elevated longer closest
to the wound site (Beneloujaephajri et al., 2013; Costa et al.,
2017; Behera et al., 2018; Nguyen et al., 2018; Toyota et al.,
2018; Hander et al., 2019; Li T. et al., 2019; Marhavý et al.,
2019). is observation also applies to other model species,
for example, fruit y (Drosophila melanogaster; Razzell et al.,
2013; Shannon etal., 2017). Mechanical damaged cells themselves
experience immediate and highest spikes in Ca2+ levels, likely
because of passive inux of Ca2+ through perforated plasma
membranes or coming from internal stores (Hander et al.,
2019). Cytosolic Ca2+ peaks are associated with corresponding
drops in cytosolic pH (Behera et al., 2018).
Calcium signaling relies on a set of channels, pumps, and
eector Ca2+-binding proteins (De Vriese et al., 2018) for
generation and readout of information in so-called Ca2+ signatures
– cell-to-cell dierences in calcium peak duration, intensity,
and repetition – as observed during wounding (Figure 1C).
Ca2+ signals can be inhibited by the application of typical
extracellular chelators (e.g., EGTA and BAPTA) and inhibitors
of Ca2+ channels (e.g., verapamil and GdCl3) at least in the
cells neighboring the damaged cells (Beneloujaephajri et al.,
2013; Hander et al., 2019; Marhavý et al., 2019). CNGC19 is
the rst known Ca2+-permeable channel that mediates propagation
of cytosolic Ca2+ elevations in the vasculature of the local leaf
(within a minute) during mechanical and herbivore damage
(Meena et al., 2019). Loss-of-function cncg19 mutants have a
decreased production of JA, glucosinolates, and are more
susceptible to herbivores (Meena et al., 2019). Free Ca2+ can
bind to EF-hand motifs present in calmodulins, calcineurin
B-like protein (CBL) and CBL-interacting protein kinase (CIPK),
calcium-dependent protein kinases (CDPKs, also referred to
as CPKs), and calmodulin-like proteins (CML). So far,
autoinhibited Ca2+-ATPase isoform 8 (ACA8) is the only known
Ca2+ pump involved in calcium signaling in the local wound
response and is regulated by phosphorylation of a CBL1-CIPK9
complex (Costa etal., 2017). e Ca2+-binding protein, CML42
is transcriptionally induced by Spodoptera littoralis feeding and
application of insect oral secretions on Arabidopsis leaves but
not by mechanical damage simulated by MecWorm (Mithöfer
et al., 2005; Vadassery et al., 2012). Glucosinolate production
is impaired in cml42 mutants in the presence of herbivores.
CML42 is responsible in part for the trichome branching
formation, a structural defense against herbivores (Dobney
et al., 2009), and in the negative modulation of JA-induced
cytosolic Ca2+ elevations and JA signaling (Vadassery et al.,
2012). On the contrary, CML37 is induced both by insect
herbivory and mechanical damage (MecWorm) and is a positive
regulator of the defense response against herbivores, as JA
accumulation and JA marker gene expression is impaired in
cml37 mutants upon herbivory (Scholz et al., 2014). e
calmodulin binding protein IQD1 is induced by wounding
and aects glucosinolate biosynthesis (Levy et al., 2005). From
a collection of CPK mutants, cpk3 and cpk13 show lower levels
of defense gene induction, independent of JA signaling, aer
wounding (Kanchiswamy et al., 2010). Interestingly, 30 min
aer mechanical or herbivore-induced damage, accumulation
of intracellular Ca2+ at wound sites was signicantly higher
in cpk3 than cpk13 or wild type (Kanchiswamy et al., 2010).
Traditionally perceived as by-products of cellular metabolism,
ROS have later been recognized to play active roles in stress
signaling and to be essential for wound responses in plants
and animals (Suzuki and Mittler, 2012). Hydrogen peroxide
(H2O2) increases both at the injury site and systemically to
reach a peak aer 4–6 h, while superoxide (O2−) is believed
to be transiently and locally generated within minutes aer
injury (Doke et al., 1991; Minibayeva et al., 2001; Orozco-
Cárdenas et al., 2001). Next to providing structural roles in
cell wall strengthening in response to mechanical damage
(Bradley et al., 1992), ROS and especially the relatively more
stable H2O2 can act as second messengers (Mignolet-Spruyt
et al., 2016). Ca2+ and ROS accumulate locally following
mechanical damage in the same cells, where Ca2+ accumulates
in a few seconds and is required to initiate a subsequent
longer-lasting increase of ROS (maximum at 10–12 min;
Beneloujaephajri et al., 2013). Ca2+ and ROS intersect at the
plasma membrane localized respiratory burst oxidase homolog
(RBOH), which are plant homologs of NADPH oxidase (NOX)
enzymes that contain Ca2+-binding EF-hand motifs. RBOHs
function in propagation of systemic ROS waves (see next
section), as well as local response, at least in Arabidopsis roots,
leading to ethylene production (Marhavý et al., 2019). Similar
to ROS, lesser-studied reactive nitrogen species (RNS), such
as NO, accumulate locally between 15 min and 2 h and aid
in wound healing by lignin and callose deposition (Huang
et al., 2004; Corpas et al., 2008; Arasimowicz et al., 2009).
ROS and RNS can aect the redox status of proteins, for
example, through cysteine modications, in biotic or abiotic
stresses (Mhamdi, 2019). Cysteine oxidations are found in the
enzymes 1-aminocyclopropane-1-carboxylic acid oxidase (ACO;
ethylene) and 12-oxophytodienoic acid reductase 3 (OPR3; JA;
McConnell etal., 2019; Pattyn etal., 2020), but the importance
for wound response needs further investigation.
Classically, MAPK phosphorylation cascades, notably WIPK
and SIPK in tobacco and homologs MPK3 and MPK6 in
Arabidopsis, are activated at timescales between accumulation
of Ca2+ (faster) and ROS (slower) with a maximum at 15min
aer wounding (Seo et al., 1995, 1999; Usami et al., 1995;
Bögre etal., 1997; Ichimura etal., 2000). Activation of upstream
kinases include MEKK1 and MEK1 phosphorylating MKK2
and MPK4 in Arabidopsis (Matsuoka et al., 2002; Hadiarto
et al., 2006), which can be reverted by the action of PP2C-
type phosphatases (Schweighofer etal., 2007). Wound-induced
MPK8 activity is detected within 10 min and is peculiar in
the sense that both MKK3 phosphorylation and Ca2+-dependent
calmodulin binding is required for full activation (Takahashi
etal., 2011). Once activated, MPK8 controls the redox balance
by negative regulation of RBOHD gene expression. Downstream
of the wound-activated MKK4/MKK5-MPK3/MPK6 cascade
and CPK5/CKP6 phosphorylation is the upregulation of ethylene
biosynthesis genes and ethylene accumulation (Li et al., 2018).
Intriguingly, next to the classical fast activation of MAPK

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cascades, a later activation controlled by JA-induced MAP3Ks
expression and a cascade involving MKK3 phosphorylation of
MPK1/2/7 can beobserved with a maximum at 1h aer mechanical
and herbivore-induced damage (Ortiz-Masia et al., 2007;
Sözen et al., 2020).
Plasmodesmata are plasma membrane-lined pores that connect
the cytoplasm of neighboring cells that allow cell-to-cell exchange
of molecules, and the regulation thereof plays important roles
in signaling of stresses, including pathogen defense and wounding
(Jacobs etal., 2003; Cheval and Faulkner, 2018). Locally elevated
levels of Ca2+ and ROS will lead to rapid closure of the
plasmodesmata within seconds to minutes (Holdaway-Clarke
et al., 2000; Cui and Lee, 2016; Xu et al., 2017). Deposition
of callose, which is mostly Ca2+-dependent (Kauss etal., 1983;
Leijon et al., 2018), will further “seal the deal” in prolonged
closing of plasmodesmata and restricting access from the wound
to intact tissues (Jacobs et al., 2003; Wu et al., 2018). In
systemic signaling, plasmodesmata could beimportant for cell-
to-cell movement of molecules or continuity of membranes
and coupling of electrical signals (Cheval and Faulkner, 2018).
Similarly, sieve plates of the phloem can be rapidly closed
within minutes to prevent leakage of nutrients and assimilates
by the deposition of callose (Mullendore et al., 2010). In
Fabaceae, specialized proteinaceous structures called forisomes
expand upon the binding of Ca2+ was released during wounding
to block the sieve plate pores (Knoblauch and Van Bel, 1998).
Interestingly, unidentied Ca2+-binding proteins in aphid
(Megoura viciae) watery saliva, which they inject in the phloem,
can chelate Ca2+ and leave sieve elements unblocked for
uninterrupted aphid feeding in Fabaceae (Will et al., 2007).
Cytosolic Ca2+ elevations during aphid feeding can beobserved
in species that lack forisomes, such as Arabidopsis, so Ca2+
chelation by aphid saliva is likely a more general phenomenon
(Vincent et al., 2017).
Systemic Wound Tides: Hydraulic Waves,
Electric Torrents, and Ca2+ Fluxes
More than a century ago, the existence of long-distance signals
of unknown nature that is able to propagate signals throughout
the plant and travel through the vascular bundle was already
hypothesized (Burdon-Sanderson, 1873; Ricca, 1916; Stahlberg,
2006). In recent years, signicant strides have been made in
understanding these systemic signals (Davies, 2006; Stahlberg
et al., 2006; Vodeneev etal., 2015; Farmer et al., 2020), which
can beattributed mainly to (1) very rapid changes in hydraulic
pressure and (2) slower propagation of electric, ROS, and Ca2+
signals, and enigmatic xylem-born chemical elicitor-dubbed
Ricca’s factor (Ricca, 1916; Figure 2A). In parallel to vascular
signaling, signals can be released from plants in volatile forms
that may activate defense in the same plant’s distal parts or
in other plants in the neighborhood (Kessler and Baldwin,
2001). Volatile signals are addressed in these recent reviews
(Bouwmeester et al., 2019; Ninkovic et al., 2019).
Wounding can cause a direct loss of the water content of
plants and in many occasions can disrupt the plant vasculature,
which has a direct eect on the turgor pressure of plant
epidermal cells (Malone and Stanković, 1991). Changes in the
hydraulic components were proposed to bepart of the systemic
damage signal that takes advantage of the organ interconnectivity
of the vasculature (Malone and Stanković, 1991; Boari and
Malone, 1993). Another measure of hydraulic signals, found
in common in dierent species including wheat, tomato, soybean,
faba bean, and others, is a change in leaf thickness in neighboring
leaves of a damaged leaf (Boari and Malone, 1993). Changes
in turgor pressure and leaf thickness are likely caused by the
retraction of water through the vascular system in a pressure
wave that travels the rigid xylem vessels (Malone and Stanković,
1991; Stahlberg and Cosgrove, 1992, 1995). Although the results
showed dierences on the magnitude of the reaction across
species and capacity of responsiveness, the data obtained for
leaf thickness starts within seconds and peaks around 1–4min,
lasting about 1 h or longer. Hydraulic signals propagate at an
estimated speed of 10–20 cm·s−1, meaning that rupture of the
water continuity by wounding can have relatively direct
repercussions on distant locations (Malone, 1992; Boari and
Malone, 1993). At present, the study of hydraulic changes
during wounding is rather unexplored, likely due to the absence
of tools that allow ecient detection of changes on pressure
over short periods of time at distant locations. A recent study
detailed the use of a non-invasive method using optical methods
that measures the changes of the diraction patterns associated
to stem displacement aer aming injury (Nožková etal., 2018).
Relatively better studied are the electrical signals, which are
based on changes in the membrane potentials (depolarization
or hyperpolarization followed by repolarization) and were recently
reviewed in Farmer etal. (2020). At least four types of electrical
signals elicited by damage are reported in the literature: wound
potential, action potential, slow wave potential (also named
variation potential), and systems potential, each displaying dierent
characteristics (Davies, 2006; Stahlberg etal., 2006; Zimmermann
et al., 2009, 2016; Farmer et al., 2020). Wound potential
depolarization spreads locally around the damaged area (<40mm
or about the length of 200 epidermal cells in cucumber hypocotyls;
Stahlberg et al., 2006). While probably sharing molecular
mechanisms with systemic electrical signals, such as inhibition
of P-type H+ pumps (Stahlberg et al., 2006), wound potentials
are technically not considered as systemic signals. Action potentials,
slow wave potentials, and systems potentials spread to distal
parts of the plant with the main dierence that slow wave
potentials are driven by hydraulic or chemical changes, as they
can travel across killed or poisoned areas (Stahlberg and Cosgrove,
1992). e slow part in slow wave potential reects a delayed
repolarization, and slow wave potentials are dampened in amplitude
in more distal parts of the plant. On the other hand, action
potentials are characterized by their all-or-none depolarization
traveling without attenuation (Favre and Agosti, 2007; Cuin
et al., 2018). Systems potentials are mainly dierent to the
aforementioned signals in that they are hyperpolarized instead
of depolarized (Zimmermann et al., 2009).
Earlier studies of electrical signals, similar to hydraulic
signals, were mainly performed using harsh damaging
treatments, such as aming. More recently, subtle mechanical
or herbivore induced wounds were also found to induce
electrical signals, likely containing mixed forms of wound

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potentials, action potentials, slow wave potentials, and systems
potentials (Salvador-Recatalà etal., 2014; Zimmermann et al.,
2016). Observations of dierent electrical signals can bevery
heterogenous and depend on several factors including (1)
severity of the damage, for example, aming triggering strong
hydraulic waves and slow wave potentials and herbivores
triggering action potentials and systems potentials, (2) the
readout method of choice, for example, stomata impaled-
pierced, agar-pierced, or blindly pierced electrodes or aphids
as living bioelectrodes, and (3) place of recording, which
mainly relates to abundance and interplay of signals from
multiple vascular strands (Salvador-Recatalà et al., 2014;
Zimmermann et al., 2016).
Identication of clade 3 glutamate receptor-like (GLR) genes,
Arabidopsis H + -ATPases (AHAs), and RBOHs that shape or
propagate the systemic signals illustrate the intertwining of electrical
signals with Ca2+ and ROS waves and their impact on the
downstream activation of JA synthesis (Koo and Howe, 2009;
Mousavi et al., 2013; Gilroy et al., 2016; Nguyen et al., 2018;
Toyota et al., 2018; Farmer et al., 2020). Mousavi et al. (2013)
identied two GLRs, homologs of mammalian ionotropic glutamate
receptors (iGluRs), for which double homozygous mutants have
reduced wound-induced systemic membrane depolarization, and
changes in JA marker gene expression. While electric signals do not
propagate to neighboring leaves in the glr3.3 glr3.6 mutant, signals
in the (local) wounded leaf are unaected (Mousavi et al., 2013;
Salvador-Recatalà et al., 2014; Salvador-Recatalà, 2016),
leading to the conclusion that GLR3.3 and GLR3.6 are “gatekeepers”
of systemic electric signals. Interestingly, loss-of-function of a
third GLR, glr3.5, leads to systemic electric signals in
non-neighboring leaves, where usually no signals are detected,
indicating that GLR3.5 acts as an o-switch (Salvador-Recatalà,
2016). Whereas GLRs are involved in propagation of slow wave
potentials, in vitro activation of CNGC19 by hyperpolarization
hints at its involvement in systems potential propagation
(Meena et al., 2019).
Wounds generated by mechanical damage results in the increase
of apoplastic glutamate concentration ([Glu]apo) of ~50 mM
within minutes at the damage site, suggesting that [Glu]apo can
act as a DAMP (Toyota et al., 2018). Glutamate, among other
amino acids, are specically perceived in plants through GLRs
(Qi et al., 2006; Toyota et al., 2018; Aleri et al., 2020; Shao
et al., 2020). GLRs are calcium-permeable channels and thereby
mediate the inux of cytosolic Ca2+ within seconds aer the
damage (Vincill et al., 2012; Mousavi et al., 2013; Nguyen et al.,
2018; Toyota etal., 2018). Similar to slow wave potentials, systemic
Ca2+ waves are observed following wounding (Kiep et al., 2015)
and did not spread to neighboring intact leaves in the glr3.3
glr3.6 mutant (Toyota et al., 2018), showing that electrical and
Ca2+ signals are closely interacting through GLRs (Nguyen et al.,
2018). In Arabidopsis systemic leaves, slow wave potentials seem
to precede peak Ca2+ signals (Nguyen et al., 2018).
Slow wave potentials travel through the vasculature toward
the center of the rosette and then disperse away from the
AB
FIGURE2 | Schematic representation of systemic response to wounding. (A) Different origins of wounding, including biotic attack (herbivore and pathogens),
mechanical damage (cutting and laser induced), and weather induced damage (freezing and hail). Depending on severity of the wound, propagation of systemic
signals ensues. Local changes in membrane potentials, increases in cytosolic Ca2+, and ROS accumulation generate a wave that quickly spreads throughout the
plant, in order to reach distant tissues. (B) Systemic-induced jasmonic acid (JA) continues to promote JA-dependent defense genes in distant tissues, leading to a
systemic growth/defense trade-off to promote plant tness.

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apex into a restricted number of parastichy leaves to initiate
distal JA accumulation and signaling (Mousavi et al., 2013;
Nguyen et al., 2018; Farmer et al., 2020; Figure 2B). e
measured speed of leaf-to-leaf electrical signal was observed
in the ~2 cm/min range, which is concordant with estimates
of signal speeds of JA accumulation measured in leaf-to-leaf
wounding studies (Chauvin etal., 2013; Mousavi etal., 2013).
e signal spreads across tissues by GLRs through the phloem
and xylem vascular tissues, especially when major veins are
damaged (Salvador-Recatalà et al., 2014; Nguyen et al., 2018;
Toyota et al., 2018). Minutes following slow wave potentials,
JA is locally and systemically synthesized leading to the
activation of the transcriptional JA responses (Mousavi etal.,
2013). Proton pumps were long expected to take part in the
return of membrane potential back to its initial status
(repolarization), but the genetic evidence was lacking (Stahlberg
and Cosgrove, 1996; Fleurat-Lessard etal., 1997). Kumari etal.
(2019) recently found that repolarization in the Arabidopsis
proton pump H + -ATPASE 1 (AHA1) decient plants took
longer compared to wild type, indicating a role for AHA1in
resetting the plant for sensing new stimuli. Additionally, aha1
mutants have higher total JA accumulation and JAZ10 expression
and reduced levels of herbivory (Kumari et al., 2019), which
is the opposite in glr3.3 glr3.6 plants (Mousavi et al., 2013;
Nguyen et al., 2018). Recently as well, Shao et al. (2020)
provided evidence that higher pH, such as during wound-
induced apoplast alkalization, greatly enhances the binding
of glutamate to GLR3.3 and GRL3.6. ey further conrmed
the eect of AHA1 on slow wave potentials. Taking in
consideration theoretical models and experimental work that
predict chemical agents transported by xylem mass ow or
sheer-enhanced dispersion propagate slow wave potentials, as
opposed to pressure waves (too fast) or chemical diusion
(too slow; Vodeneev et al., 2012; Evans and Morris, 2017;
Blyth and Morris, 2019), [Glu]apo might well be (part of)
the ideal candidate(s) for Ricca’s long-sought chemical factor(s)
that propagate the slow wave potential (Ricca, 1916). Sudden
changes in the negative and positive pressure of xylem and
phloem, respectively, followed by osmotic re-equilibration,
might help to pull in [Glu]apo or other chemical elicitors in
the vasculature (Farmer et al., 2020).
In parallel with systemic electrical signals, Ca2+ and ROS
waves are induced by wounding, among other stresses, and
depend on RBOHs (Miller et al., 2009; Choi W.-G. et al.,
2014; Kiep et al., 2015; Evans et al., 2016; Choi et al., 2017;
Toyota et al., 2018). In systemic tissues, mechanical damage
and H2O2 inducible gene expression overlap considerably more
than any other purportedly ROS-induced transcripts, including
O2− and singlet oxygen (Miller et al., 2009). One of these
H2O2-inducible genes is zinc nger of Arabidopsis thaliana12
(ZAT12). ZAT12 expression, using luciferase reporter lines, is
induced strongly within 10 min aer wounding in the local
leaf, while it spreads systemically at 8.4cm/min to full expression
within the hour and both are impaired in an rbohd mutant
(Miller etal., 2009). New ways of visualizing ROS will improve
the further study of systemic signaling in species other than
Arabidopsis, including crops (Fichman etal., 2019; Lew et al.,
2020). ROS waves can beinhibited by the Ca2+ channel blocker
lanthanum (La3+; Miller et al., 2009). Next to the N-terminal
Ca2+-binding EF-hand motif (Suzuki et al., 2011), RBOHD
activity is regulated through phosphorylation at its N-terminus
by the calcium dependent kinase CPK5 upon elicitation with
g22, a bacterial agellin peptide and elicitor of innate immunity
(Suzuki et al., 2011; Dubiella et al., 2013). Wound-induced
Ca2+ waves are suppressed in loss-of-function mutants of the
vacuolar cation channel two pore channel 1 (TPC1), whereas
local Ca2+ elevation was largely unaected (Kiep etal., 2015).
RBOHD can interact with dierent partners involved in immune
response such as the receptor kinases EFR and FLS2, and
botrytis-induced kinase1 (BIK1; Laluk et al., 2011; Kadota
et al., 2014). Furthermore, cysteine rich receptor-like kinase
2 (CRK2) controls g22-induced H2O2 production through
direct interaction with RBOHD and phosphorylation of its
cytosolic C-terminus (Kimura et al., 2020). Whether these
interactions are important for systemic wound signaling warrants
investigation. A unifying concept of molecular mechanisms
underpinning wound-induced systemic signals is within reach
(Gilroy et al., 2016; Farmer et al., 2020) but will require the
discovery of additional genetic players.
WOUND-INDUCED HORMONE
SIGNALING
Upon wounding, several hormones, including JA, ethylene,
ABA, auxin, and their respective cross-talks, are indispensable
for damage perception and eliciting key downstream responses.
First on the Scene: Jasmonic Acid
Signaling
Jasmonic acid is a phytohormone involved in many aspects
of plant stress responses and development. Probably the most
renowned is the regulation of mechanical wounding and
immune responses against herbivores or necrotrophic pathogens,
which trigger the biosynthesis of JA and of its bioactive form
jasmonoyl--isoleucine (JA-Ile) not only at the damage site
but also systemically in unharmed tissues (Glauser et al.,
2008; Koo and Howe, 2009; Goossens et al., 2016). JA
biosynthesis begins with release of α-linolenic acid from
chloroplast membrane phospholipids, which is then converted
into cis-(+)12-oxo-phytodienoic acid (OPDA) through the
sequential action of chloroplast-located enzymes, such as the
13-lipoxygenases (13-LOX; Wasternack and Feussner, 2018).
OPDA is then exported from the chloroplast by JASSY, a
protein localized to the outer chloroplast envelope (Guan
etal., 2019), and transported into the peroxisomes, presumably
by the ABC transporter Comatose (AtABCD1/CTS) and acyl-
CoA-binding protein 6 (ACBP6; eodoulou et al., 2005; Ye
et al., 2016). Once in the peroxisome, OPDA is reduced by
OPDA reductases 2 and 3 (OPR2 and OPR3) and subsequently
oxidized through two distinct pathways to form JA (Schaller
and Stintzi, 2009; Chini etal., 2018). e bioactive molecule
JA-Ile is synthetized by the JA resistant 1 (JAR1) enzyme

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and transported to the nucleus within minutes aer plant
damage (Suza and Staswick, 2008). Nuclear transport of JA-Ile
is mediated by the jasmonate transporter 1 (JAT1), a member
of the ABC transporter family known to transport small
molecules such as auxins, abscisic acid, or strigolactones (Li
etal., 2017). In the nucleus, JA-Ile is perceived by a co-receptor
complex composed of the JA ZIM-domain (JAZ) repressor
proteins and the coronatine insensitive 1 (COI1) F-box protein
that associates with CUL1, Rbx1, and the Skp1-like proteins
ASK1 and ASK2 to assemble the SCF-COI1 ubiquitin-ligase
complex (ines et al., 2007; Fonseca et al., 2009; Sheard
et al., 2010; Williams et al., 2019). Hormone perception
requires a JAZ degron that bridges COI1 to JA-Ile (Sheard
et al., 2010). In addition, inositol pentakisphosphate (InsP5)
was identied as a critical structural component of the receptor
complex (Sheard et al., 2010). Plants with increased InsP5
showed accentuated wounding responses, suggesting that InsP5
contributes to the assembly and function of the SCF-COI1
complex (Mosblech et al., 2011). Following JA-Ile binding,
the SCF-COI1 complex ubiquitinates the JAZs, which targets
them for proteasomal degradation. ereby, several transcription
factors (TFs), such as the MYCs that are otherwise bound
by the JAZ proteins, are released and can activate the JA
response (Chini et al., 2007; Fonseca et al., 2009; Goossens
et al., 2016). JA-Ile perception and signaling leads to the
systemic alteration of a growth-defense balance to promote
plant tness (Wasternack and Feussner, 2018). One of the
most characteristic features of JA is the transcriptional
reprograming of a wide array of enzymes leading to production
of specialized metabolites, including terpenes, glucosinolates,
phenolics, or alkaloids (Pauwels etal., 2008; Hickman etal., 2017;
Zander et al., 2020).
On the contrary, JA represses signaling pathways that lead
to plant growth to reallocate resources toward defense (Hou
etal., 2010; Major etal., 2017; Guo etal., 2018). It was shown
that a growth penalty is restored to dierent extents in moderate
(jazQ) or in severe (jazD) JAZ depleted mutants by the
introgression of a phytochrome B (phyB) mutation, which was
explained by the fact that JA and phyB transcriptional networks
are uncoupled (Campos et al., 2016; Major et al., 2020).
Interestingly, these ndings show that the JA regulated growth-
defense trade-o is not merely directed by the need of relocating
metabolic resources, which opens interesting leads for plant
improvement for agricultural or industrial purposes. Because
of the importance in tuning the growth-defense balance, JA
and growth promoting pathways are cross-regulated through
dierent pathways in response to changing environments. DELLA
proteins are plant growth repressors whose degradation is
promoted by gibberellins (Davière and Achard, 2016). DELLAs
have been reported to interact with JAZs to thereby compete
with MYC2 and, thus, modulate JA responses (Hou et al.,
2010; Wild et al., 2012; Leone et al., 2014). However, the
importance of DELLAs in the cross-regulation of the JA pathway
has recently been challenged by a study that shows no major
role of DELLAs in restricting shoot growth of jaz mutants
(Major et al., 2020). Wounding dramatically modies the
growth-to-defense balance, resulting in stunted vegetative growth
eects being directly linked to the activation of JA synthesis
(Yan et al., 2007).
A key function of JAs produced in damaged organs is to
travel systemically across tissues in order to reprogram future
growth and optimize plant defense strategies (Huot et al.,
2014; Guo etal., 2018; Ballaré and Austin, 2019). Upon damage,
plants tightly regulate biosynthesis, transport, and catabolism
of JAs (Browse, 2009; Chini et al., 2016; Howe et al., 2018;
Fernández-Milmanda et al., 2020; Yang et al., 2020). JA
biosynthesis in Arabidopsis depends on LOX2, LOX3, LOX4,
and LOX6. Each of these LOXs contribute in a dierent way
to regulate JA biosynthesis and transport upon wounding
(Chauvin et al., 2013, 2016; Grebner et al., 2013; Yang et al.,
2020). LOX2 is expressed throughout so aerial tissues, whereas
LOX3, LOX4, and LOX6 are expressed in the phloem and
xylem of leaves (Chauvin et al., 2013, 2016). LOX2 is highly
induced in the close vicinity of wounds in cotyledons and is
necessary to ensure leaf to root axial JA transport (Gasperini
etal., 2015). Upon wounding, LOX6 participates in the radial
export of JAs from the leaf vasculature to the blade (Gasperini
et al., 2015). It was recently suggested that LOX3 and LOX4
repress leaf growth upon wounding by acting on stem cell
populations that determine the rate of leaf primordia
development (Yang et al., 2020). Furthermore, the activity of
LOX3 and LOX4 in leaf growth is related to the vacuolar
cation channel TPC1 through a mechanism that remains
unclear (Bonaventure et al., 2007; Yang et al., 2020).
e aforementioned studies together with the discovery of
GLR-aided electrical signaling reveal that wounded leaves rely
on at least two kinds of JA-dependent mechanisms to alert
distal organs, being dierent whether the signal translates from
leaf-to-leaf or from leaf-to-root (Mousavi etal., 2013; Gasperini
et al., 2015; Schulze et al., 2019). Shoot wounding not only
activates electrical signals but also triggers relocation of JA-Ile
precursors, tentatively OPDA, OPC-4, OPC-6, OPC-8, and JA
from wounded shoots toward undamaged roots (Schulze etal.,
2019). Mobile OPDA and its derivatives activate JA signaling
through their conversion into JA-Ile at the distal sites, and
while leaf-to-leaf signaling relies on electrical and hormone
translocation mechanisms, and leaf-to-root signaling seems to
exclusively rely on hormone (precursor) translocation (Schulze
et al., 2019). In complement to these studies, the development
of the uorescent biosensor Jas9-VENUS allowed visualization
of the dynamic distribution of JA-Ile in wounded plants (Larrieu
et al., 2015). Cotyledon wounding generated a distal increase
of JA-Ile through vascular tissues of the root following two
distinct temporal dynamics. e rst phase started with a rapid
increase of distant JA-Ile propagating at a speed <1 cm/min,
few minutes aer wounding, then a second slower phase that
started 30 min and lasted for at least 90 min (Larrieu et al.,
2015). e nature behind these phases needs further investigation
to beconciliated with latter results, suggesting that leaf-to-root
signaling exclusively relies on hormone translocation, which
is likely a slower process than the initial observed phase.
Although glutamate was characterized as triggering rapid
slow wave potentials resulting in the activation of the JA
pathway, little is known about additional DAMPs triggering

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distant and/or local JA signaling. A large set of cell wall-
related DAMPs have been characterized for triggering wound
responses; however, despite the fact that JA is one of the
most well-characterized phytohormonal pathways activating
wound responses, mechanisms clearly connecting cell wall
perception to JA are missing (Mielke and Gasperini, 2019;
Bacete and Hamann, 2020). Exogenous application of cell wall
degrading enzymes or the cell wall fragments OGs (DP10–
DP15) or xyloglucans (Xh) results in the activation of JA
signaling (de Azevedo Souza etal., 2017; Claverie etal., 2018;
Engelsdorf et al., 2018). Xh elicited resistance against the
necrotrophic pathogen Botrytis cinerea was abolished in JA
biosynthesis (dde2) and signaling (coi1-40) mutants, suggesting
the specic activation of the JA pathway by Xh (Claverie
et al., 2018). In Nicotiana attenuata, the combination of
wounding with the fatty acid conjugates N-linolenoyl-l-Gln,
N-linolenoyl-l-Glu, N-linoleoyl-l-Gln, and N-linoleoyl-l-Glu
strongly activated JA biosynthesis and subsequent herbivore
defense responses (Wu et al., 2007). Future studies should
address how cell wall disruption leads to local JA signals and
if they connect to systemic responses. In this respect, Arabidopsis
mutants of the xylem-specic cellulose synthases, irregular
xylem 3 and 5 (irx3 and irx5), severely aect the shape and
speed of slow wave potentials; however, JAZ10 expression in
systemic leaves, as a measure of JA signaling, is only slightly
aected (Kurenda et al., 2019).
Likewise, the molecular events operating downstream of
the Ca2+ inux, preceding the rapid biosynthesis and
redistribution of JAs are hardly understood. Phosphorylation
is postulated to beone of the major cellular modes of action
for translating dened Ca2+ signatures into specic downstream
reactions (Dodd et al., 2010; Yip Delormel and Boudsocq,
2019). Several existing lines of evidence point to the importance
of Ca2+/phosphorylation for JA signaling in the context of
wound responses. Furthermore, Ca2+ signaling has been
repeatedly hypothesized as a mechanism preceding JA signaling,
which suggests that Ca2+ signals may not only relate to GLRs
but also to other alternative pathways activating JA signaling
(Kenton etal., 1999; Bonaventure etal., 2007; Scholz et al.,
2014; Lenglet et al., 2017). e JA-associated VQ motif 1
(JAV1) protein associates in a complex with JAZ8-WRKY51
to represses the expression of JA biosynthesis genes. Wounding
or insect attack activate a Ca2+Calmodulin dependent pathway
that phosphorylates JAV1, leading to its degradation to thereby
activating transcription of JA biosynthesis genes (Yan et al.,
2018). Beyond the potential importance of phosphorylation
for Ca2+ induced JA biosynthesis, it was recently shown that
wounding triggers JA signaling in the stomata through the
activity of the Ca2+ receptor kinase complex CBL1-CIPK5
(Förster et al., 2019). Furthermore, a recent study showed
that the rice homolog of brassinosteroid insensitive 2 (BIN2),
OsGSK2 kinase, phosphorylates OsJAZ4 to promote its
degradation in a COI1-dependent manner, thereby posing
a new mechanism of growth-defense regulation (He et al.,
2020). Additionally, wound-activated MAPK signaling
mechanisms have been reported to regulate the JA pathway
(Wu et al., 2007; De Boer et al., 2011). WIPK and SIPK
regulate wound responses including JA biosynthesis in
Solanaceae species. In N. attenuata, leaf wounding together
with the herbivore oral secretion treatment elicits strong
SIPK and WIPK activities resulting in the biosynthesis of
JA, SA, and JA-Ile/JA-Leu conjugates and ethylene biosynthesis.
e SIPK and WIPK activate the transcription of defense
related genes in both wounded and unwounded regions of
the local leaf but not in systemic adjacent leaves (Wu etal.,
2007). In tobacco, the JA-factor stimulating MAPKK1 (JAM1)
protein regulates transactivating activities of the ORC1 and
MYC transcription factors in a JA dependent manner (De
Boer et al., 2011). Altogether, this evidence underscores that
phosphorylation is an important post-translational modication
in the regulation of plant wound responses and JA signaling;
however, to date, these mechanisms have only been explored
to a limited extent.
Rather Late Than Never: Accumulation of
Ethylene, ABA, and Auxin During Wound
Response
Ethylene has many roles in plant development and stress
response (Pattyn etal., 2020), including fruit ripening, where
inhibition is a critical target for improved storage (shelf-life)
of fruit and vegetables post-harvest (Barry and Giovannoni,
2007; Saltveit, 2016). Wound-induced ethylene accumulation
is thought to proceed via transcriptional upregulation of its
rate-limiting biosynthetic enzyme 1-aminocyclopropane-l-
carboxylate (ACC) synthase (ACS) resulting in a lag-time
of 20–30 min before the rst accumulation of ethylene and
a peak within hours aer wounding (Boller and Kende, 1980;
Kato etal., 2000; Marhavý etal., 2019). Ethylene production
depends on both ROS and Ca2+ increases (Marhavý et al.,
2019) and is transduced by MAPK and CDPK-dependent
phosphorylation for activation of ACS gene expression locally
at wound sites (Wu et al., 2007; Li etal., 2018; Sözen et al.,
2020). Possible involvement of DAMPs cannot be ruled out,
as Peps induce the accumulation of ethylene within 5 h
aer exogenous peptide application (Bartels et al., 2013).
Furthermore, electrical signaling might lead to systemic
increases of ethylene production in distal leaves (Dziubinska
et al., 2003; Tran et al., 2018; Farmer et al., 2020). In the
young root meristem, JA has been shown to be involved in
transmitting the single cell damage signal (Zhou etal., 2019),
whereas in older non-dividing root cells, a predominant role
for ethylene has been demonstrated (Marhavý et al., 2019).
Here, death of a single cell, through laser ablation or during
the early stages of nematode infection, causes a distinct
ethylene-dominated response (Marhavý et al., 2019).
Abscisic acid (ABA) accumulation is doubled within 24 h
aer wounding and induces, among other cues, the expression
of the proteinase inhibitor II gene in potato and tomato (Pēna-
Cortes et al., 1989; Peña-Cortés et al., 1995; Dammann etal.,
1997). Arguably, ABA is best known for its role in drought-
induced stomatal closure (Cardoso and McAdam, 2019).
erefore, it should come as no surprise that ABA accumulation
likely depends on the level of humidity during wounding. As

Vega-Muñoz et al. Plant Wound Response
Frontiers in Plant Science | www.frontiersin.org 15 December 2020 | Volume 11 | Article 610445
a case in point, Arabidopsis plants accumulate ROS normally
and develop wound induced resistance (WIR) to the fungus
Botrytis cinerea in high humidity (L’Haridon et al., 2011).
However, keeping plants 1.5h in dry conditions aer wounding,
reduces ROS, WIR, and callose accumulation, which is linked
to enhanced accumulation of ABA and is reversed in ABA
biosynthetic enzyme decient mutants aba2 and aba3 (L’Haridon
etal., 2011). In this study, ABA biosynthesis genes are induced
15 min aer wounding only in the dry condition. Probably,
dierences in experimental set-ups, therefore, fail to detect
changes in wound-induced ABA accumulation and gene
transcription (Ikeuchi etal., 2017). Interestingly, an application
of exogenous ABA leads to enhanced local cell death surrounding
wound sites in Arabidopsis, and the transcription factor botrytis
sensitive1/MYB108 (BOS1/MYB108) is a negative regulator of
this ABA-dependent cell death (Cui et al., 2013). Mutant bos1
plants display runaway cell death aer wounding, which interacts
with ABA, cuticle permeability, and resistance to B. cinerea
(Cui et al., 2013, 2016, 2019).
Accumulation of auxin at wound sites mainly has a role
in the subsequent repair process that bridges or protects
wounds and regeneration of lost tissue. Tissue reunion following
incision or upon graing requires reactivation of cell division,
not so much to generate callus, but rather to bridge the cut
and allow reconnection of the vascular tissue. Upon incision
of the inorescence stem, the NAC-type transcription factor
NAC071 and ERF113 are activated in order to assist in the
reunion process (Asahina et al., 2011). On the one hand,
ERF113, an AP2/ERF-type transcription factor, is rapidly
induced within 1 day following incision at the bottom part
of the cut site in a JA-dependent manner. On the other
hand, NAC071 is induced in the top part of the incision
between 1 and 3 days as a result of auxin accumulation,
and both TFs execute dierent functions in the reunion
process (Asahina etal., 2011). Auxin response during graing
is symmetric between top and bottom of the adjoined gra
junction and occurs within 12h, consistent with earlier reports
of auxin-induced transcription at 1–3 days aer cutting (Yin
etal., 2012; Melnyk etal., 2015, 2018; Matsuoka etal., 2016).
Upon full excision of the leaf between the blade and petiole,
callus is generated very locally at the cut site and an adventitious
root can sprout within 8 days following excision (Liu et al.,
2014). Auxin accumulates within a day at the wound site
and directly activates expression of the WUSCHEL related
homeobox 11 (WOX11) transcription factor, which works
redundantly with WOX12 to enable the transition of the
local cambium cells to root founder cells within 4 days
following the cut (Liu et al., 2014; Hu and Xu, 2016).
Accumulating evidence from recent publications on root
regeneration emphasizes the importance of auxin during the
replenishment of a single cell, a cluster of damaged root
cells, or even regeneration of a complete de novo root tip
(Canher et al., 2020; Hoermayer et al., 2020; Matosevich
et al., 2020). Depending on the severity and type of damage,
the mode of action that allows for sucient auxin accumulation
in order to facilitate the regeneration process varies. Upon
death of a single cell, for example, following laser ablation,
a strictly localized auxin signaling, independent of biosynthesis
or active transport, coordinates the wounding response
(Hoermayer etal., 2020). Upon death of a group of vascular
stem cells, for example, by bleomycin-induced DNA damage,
the natural auxin ow is disrupted through downregulation
of auxin transporters, resulting in an auxin redistribution,
much alike rocks in a stream. However, similar to single cell
death, no auxin biosynthesis could be observed during the
recovery from vascular stem cell death (Canher etal., 2020).
However, following full root tip excision, YUCCA9-dependent
auxin biosynthesis was found to be indispensable to allow
regeneration of a de novo tip (Matosevich etal., 2020). Among
the key regeneration-related and wound-responsive transcription
factors, several members of the AP2/ERF-type of transcription
factors can be found, including ERF115, wound-induced
dedierentiation 1 (WIND1) and several plethora (PLT)
members (Delessert et al., 2004; Iwase et al., 2011; Ikeuchi
etal., 2013; Heyman etal., 2016). Although originally identied
as a rate-limiting factor controlling stress-induced quiescent
cell divisions, ERF115 represents an important wound-
responsive gene (Heyman et al., 2013, 2016). Being the death
of a single cell, stem cell damage or even removal of the
entire root tip, ERF115 expression is instantly activated within
1–2h in the adjacent cells and plays a key role in stimulating
these cells to activate the cell division program (Heyman
et al., 2016; Zhang et al., 2016). Although not being the
initial trigger, auxin is required to maintain ERF115 expression
following tissue damage (Canher et al., 2020; Hoermayer
etal., 2020), leaving the question open about the initial trigger
activating this key regeneration granting factor following
wounding.
FUTURE PERSPECTIVES
e eld has come a long way since the rst observations
and descriptions of plant wound response more than a century
ago (Burdon-Sanderson, 1873; Ricca, 1916; Bloch, 1941; Lipetz,
1970). Notwithstanding detailed molecular knowledge gathered
in the last decades on several aspects, major areas of study
are still largely unexplored. Keeping in the spatiotemporal spirit
of the review, some of these areas can be dened from local
to systemic and fast to slow.
What is the fate of damaged cells in the wound and are
they actively involved in determining the outcome of the wound
response? is is exemplied by the activation of metacaspases
and maturation of Peps in damaged cells (Hander etal., 2019),
which shows that “post-mortem” cells can still be active
(Bollhöner et al., 2013). Furthermore, what are the chain of
events that proceed in the dying cells bordering the damaged
cells as observed in leafs (Cui et al., 2013; Iakimova and
Woltering, 2018), is there a point of no return and how does
it change the wound response in the neighboring tissue? While
more DAMPs are being discovered, possible mechanisms that
are in place to avoid unwanted or exaggerated wound response
by maturation, possible controlled release, and turnover of
DAMPs become important. Furthermore, are there dierent

Vega-Muñoz et al. Plant Wound Response
Frontiers in Plant Science | www.frontiersin.org 16 December 2020 | Volume 11 | Article 610445
dynamics of DAMP release, for example, fast elevation of eATP
and [Glu]apo (Song etal., 2006; Toyota etal., 2018), compared
to potential slow release of OGs due to upregulation of
polygalacturonases aer wounding (Bergey etal., 1999)? Some
studies have detailed the release of DAMPs aer wounding
(Tabl e 1 ) or extrapolate from studies in animal model species.
However, most DAMPs in plants have not been directly measured
in the apoplast or vasculature during wounding, while there
is an abundance of indirect measurements (e.g., exogenous
application). To fully understand the dynamics of DAMP release
and its impact on wound response, direct measurements are
needed in the future.
In this review, wehad to limit ourselves to reports dealing
with wounding. Certainly, molecular components that are
increasingly found in other abiotic or biotic stresses for local
and systemic signaling likely play roles as well in wounding.
As an illustration, ROS-mediated activation of Ca2+ channels
by the receptor kinase HPCA1 (Wu etal., 2020) or mechanisms
that have been described for systemic signaling by stresses
other than wounding (Gilroy etal., 2016; Szechyńska-Hebda
et al., 2017; Farmer et al., 2020). Local implications and
responses of cells to wounding change in dierent tissues.
For example, mesophyll cells are dierently connected as
xylem or phloem cells that form conduits. Disruption of tissue
integrity will therefore have dierent repercussions, which is
obvious in the slow-down of electrical, Ca2+, and ROS waves
when they move from vasculature to inner tissues (Salvador-
Recatalà et al., 2014; Evans et al., 2016; Toyota et al., 2018).
Similarly, non-dividing full-grown cells and tissues will have
dierent needs than expanding tissues and meristem cells,
which are more plastic and essential to replace. e dierences
in these tissue-specic wound responses are only starting to
be addressed (Hoermayer and Friml, 2019; Li T. et al., 2019;
Marhava etal., 2019; Marhavý etal., 2019; Zhou etal., 2019).
Although such complex problems are dicult to predict
(Lehmann et al., 2020), detailed knowledge on plant wound
response will become even more needed as weather- and
herbivore-induced damage is projected to increase with climate
change (Deutsch et al., 2018). Development of new techniques
for investigating wound response, such as MecWorm (Mithöfer
etal., 2005) and SpitWorm that adds oral secretion to simulated
herbivore-induced damage (Li G. etal., 2019), or laser-mediated
wounding (Hoermayer and Friml, 2019; Marhavý et al., 2019)
will help advance the eld. Application of this newfound
knowledge has the ability to improve graing, regeneration,
and crop production (Santamaria et al., 2013; Si et al., 2018;
Coppola et al., 2019; Notaguchi et al., 2020; Zhang and
Gleason, 2020).
AUTHOR CONTRIBUTIONS
IV-M, DD-F, and AF-F made the table and gures. IV-M
and DD-F wrote the part on DAMPS. AF-F and SS wrote
the part on local and systemic wound signaling. AR, JH, and
SS wrote the part on hormones. All authors made comments
on the manuscript, which were integrated by SS. All authors
contributed to the article and approved the submitted version.
FUNDING
DD-F and IV-M were nancially supported by the Conacyt
de México (grants 278283 and 661846, respectively) and SS
by the Research Foundation-Flanders (grant FWO14/PDO/166).
ACKNOWLEDGMENTS
DD-F and IV-M gratefully acknowledge the nancial support
from the Conacyt de México. We thank Martine De Cock for
her help in preparing the manuscript.
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