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Small heat shock proteins, protein degradation and protein aggregation diseases

Taylor & Francis
Autophagy
Authors:
Michel Vos at University of Groningen
Michel Vos
Marianne P Zijlstra
Marianne P Zijlstra
Marianne P Zijlstra
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Serena Carra at Università degli Studi di Modena e Reggio Emilia
Serena Carra
Ody Sibon at University of Groningen
Ody Sibon
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Abstract

Small heat shock proteins have been characterized in vitro as ATP-independent molecular chaperones that can prevent aggregation of un- or mis-folded proteins and assist in their refolding with the help of ATP-dependent chaperone machines (e.g., the Hsp70 proteins). Comparison of the functionality of the 10 human members of the small HSPB family in cell models now reveals that some members function entirely differently and independently from Hsp70 machines. One member, HSPB7, has strong activities to prevent toxicity of polyglutamine-containing proteins in cells and Drosophila, and seems to act by assisting the loading of misfolded proteins or small protein aggregates into autophagosomes.
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www.landesbioscience.com Autophagy 101
Autophagy 7:1, 101-103; January 2011; © 2011 Landes Bioscience
AUTOPHAGIC PUNCTUM AUTOPHAGIC PUNCTUM
Punctum to: Vos MJ, Zijstra MP, Kanon B, van
Waarde-Verhagen MAWH, Brunt ERP, Oosterveld-
Hut HMJ, et al. HSPB7 is the most potent polyQ
aggregation suppressor within the HSPB family
of molecular chaperones. Hum Mol Genet 2010;
19:4677–93; PMID: 20843828; DOI: 10.1093/hmg/
ddq398.
Key words: heat shock protein, HSPB,
polyglutamine diseases, autophagy,
Hsp70
Submitted: 10 /12/10
Revised: 10 /13/10
Accepted: 10 /13/10
Previously published online:
www.landesbioscience.com/journals/
autophagy/article/13935
DOI: 10.4161/auto.7.1.13935
*Correspondence to: Harm H. Kampinga;
Email: h.h.kampinga@med.umcg.nl
Small heat shock proteins have been
characterized in vitro as ATP-
independent molecular chaperones that
can prevent aggregation of un- or mis-
folded proteins and assist in their refold-
ing with the help of ATP-dependent
chaperone machines (e.g., the Hsp70
proteins). Comparison of the functional-
ity of the 10 human members of the small
HSPB family in cell models now reveals
that some members function entirely dif-
ferently and independently from Hsp70
machines. One member, HSPB7, has
strong activities to prevent toxicity of
polyglutamine-containing proteins in
cells and Drosophila, and seems to act
by assisting the loading of misfolded
proteins or small protein aggregates into
autophagosomes.
Polyglutamine (polyQ) diseases are char-
acterized by an unstable and abnormal
expansion of a CAG repeat within the
protein-coding region of the affected
genes, resulting in an elongation of the
glutamine repeat within the protein. This
specific mutation or elongation, promotes
aggregation of the mutant protein towards
insoluble aggregates (Fig. 1) and causes
the development of neurological disorders
like Huntington disease and spinocerebel-
lar ataxias.
It remains unclear how protein aggre-
gates lead to degeneration. In fact, the for-
mation of large(r) amyloid-like inclusions
(Fig. 1) that usually hallmark these dis-
eases, likely reflect a (last) attempt of the
protein quality control system to prevent
the detrimental effects of the more toxic
Small heat shock proteins, protein degradation and protein aggregation
diseases
Michel J. Vos,† Marianne P. Zijlstra,† Serena Carra, Ody C.M. Sibon and Harm H. Kampinga*
Department of Cell Biology; Section of R adiation and Stress Cell Biology; University Medical Center Groningen; University of Groningen;
Groningen, The Netherlands
†These authors contributed equally to this work.
intermediate-size, amorphous aggregates.
However, by using several experimental
model systems it was shown that early pre-
vention or disposal of toxic protein aggre-
gates by the protein quality control system
can ameliorate disease. In our recent paper,
we show that members of the family of
human small heat shock proteins (HSPB)
act at different steps in protein quality
control with differential potential to pre-
vent toxic aggregation of polyQ proteins.
The family of human HSPB proteins
comprises 10 members. In cell-free assays,
some of them act as ATP-independent
“holdases,” meaning that they can main-
tain unfolded or misfolded proteins in a
folding competent, nonaggregated state,
but they cannot release them actively.
The latter implies that they alone can-
not help client refolding to an active
state; here, too, they require assistance of
ATP-regulated chaperones, in particular
the Hsp70 machines. In cellular assays,
we now confirm such a holdase activity
(Fig. 1, step I) for some of these members
(HSPB1, HSPB4 and HSPB5) and show
that they support refolding of a firefly
luciferase model protein, an action for
which they indeed depend on an active
Hsp70 machine. However, this activity is
not associated with significant prevention
of aggregation of polyQ proteins. This
suggests that maintenance of the refold-
ing-competent state of polyQ proteins,
which theoretically also may increase
the time window for degradation by, for
example, the proteasome (Fig. 1, step II),
is ultimately rather ineffective in prevent-
ing polyQ aggregation and toxicity.
102 Autophagy Volume 7 Issue 1
of HSPB7 is strongly reduced in ATG5-
/- cells that are impaired in autophagy.
Unlike HSPB8, however, HSPB7 does
not cause an increase in overall autophagic
activity, meaning that the endogenous
autophagic routes are sufficiently active to
support HSPB7-mediated protection.
How HSPB7 interacts with the auto-
phagic machinery remains to be elu-
cidated. The action of HSPB7 is not
affected by ‘poisoning’ the activity of
the cellular HSP70 machinery, suggest-
ing that a client transfer model via ATP
dependent chaperones, as suggested for
HSPB8 activates eIF2alpha, hereby induc-
ing autophagy and translational inhibition
of polyQ protein expression (Fig. 1, Step
V). Comparing all members, we show that
HSPB7 is in fact the most potent inhibi-
tor of polyQ aggregation within the HSPB
family. HSPB7 reduces polyQ toxicity in
cells and can prevent eye-degeneration
in a Drosophila model for spinocerebel-
lar ataxia type 3. We show that HSPB7
does not act via supporting proteasomal
degradation of polyQ proteins or aggre-
gates. Rather, like HSPB8, HSPB7 activ-
ity is related to autophagy, as the activity
Surprisingly, a number of small HSPB
members that were tested were unable to
support refolding. Whereas we only tested
ectopically expressed heat-denatured
luciferase as a substrate, leaving open the
possibility that these members have sub-
strate-specific refolding activities, it was
striking to note that four members that
all lacked luciferase refolding activity
(HSPB6, HSPB7, HSPB8 and HSPB9)
were all able to reduce polyQ aggregation.
Of these four chaperones, only HSPB8
has previously been identified as a suppres-
sor of polyQ aggregation. Intriguingly,
Figure 1. Model for the dierential processing of misfolded or/and unfolded proteins by dierent members of the human family of small Heat Shock
Proteins (HSPB). HSPB members are presented as dynamic oligomers (HSPB1, B4, B5) and/or dimers, the presumed minimal oligomeric structure of
most small HSP. For explanation of the various steps (I–V ) see the main text.
www.landesbioscience.com Autophagy 103
HSPB member-related actions in refold-
ing or supporting proteasomal degrada-
tion, may not apply here. Also, this makes
a role of the Hsp70-dependent chaperone
mediated autophagy (CMA) unlikely. As
we show that HSPB7 can interact directly
with polyQ aggregates, and most likely
cannot actively regulate client release as
it lacks ATPase activity, a model can be
envisioned that HSPB7 may enhance rec-
ognition of polyQ proteins or aggregates
by or enclosure into, (pre)autophagosomal
vesicles (Fig. 1, step IV). Supportive for
such a model are findings showing that
HSPB7 can bind to alpha-filamin, a pro-
tein that anchors membrane proteins to
the actin cytoskeleton. In conjunction
with HDAC6—that recruits the actin
remodeling machinery, required for the
fusion of autophagosomes to lysosomes—
this would support efficient and selec-
tive degradation of aggregates without
requiring the need for autophagy induc-
tion. Such a model also would imply that
HSPB7 is co-degraded with its clients.
Consistently, we find that the levels of
ectopically expressed HSPB7 are always
much lower than those of, for example,
the folding-supporting HSPB1 or HSPB5.
The data presented in our paper thus
show two interesting implications. First,
they demonstrate that members of the
small HSPB family are functionally dis-
tinct. This goes beyond client specificity
only, since the different HSPB members
handle the same client differently. In fact,
we have now data to show that HSPB9,
one other member that suppresses polyQ
aggregation, utilizes the proteasomal
route for client degradation (Fig. 1, step
III). A future challenge will be to unravel
what specifies this differential processing
by these various members and how these
processes are controlled and integrated
into the protein quality control network.
The second implication is that nonspecific
induction of autophagy, with all poten-
tial side effects, may not be required to
enhance clearance of polyQ aggregates.
By getting more insight in how expres-
sion and function of HSPB7 is regulated,
one might be able to activate the selec-
tive clearance of harmful proteins by the
endogenous autophagy machinery.
... Direct sHsp interactions with misfolded proteins can prevent further irreversible misfolding events and facilitate client triage by other chaperones that more actively influence client fate through specific proteostasis pathways (Hartl et al., 2011;Vos et al., 2011;Ungelenk et al., 2016). Generally, HspB1, HspB4, and HspB5, which are all heat shock responsive, are commonly reported to play a role in substrate refolding (Ehrnsperger et al., 1997;Vos et al., 2010, Vos et al., 2016, while HspB6, HspB7, and HspB8 have been shown to preferentially promote the degradation of clients through autophagy (Fuchs et al., 2009;Vos et al., 2010;Vos et al., 2011;Carra et al., 2013;Vos et al., 2016). ...
... Direct sHsp interactions with misfolded proteins can prevent further irreversible misfolding events and facilitate client triage by other chaperones that more actively influence client fate through specific proteostasis pathways (Hartl et al., 2011;Vos et al., 2011;Ungelenk et al., 2016). Generally, HspB1, HspB4, and HspB5, which are all heat shock responsive, are commonly reported to play a role in substrate refolding (Ehrnsperger et al., 1997;Vos et al., 2010, Vos et al., 2016, while HspB6, HspB7, and HspB8 have been shown to preferentially promote the degradation of clients through autophagy (Fuchs et al., 2009;Vos et al., 2010;Vos et al., 2011;Carra et al., 2013;Vos et al., 2016). However, this simple categorization of HspBs does not hold true in many instances, including many examples discussed in this review. ...
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... HSPBs are able to bind unfolded/misfolded substrates and subsequently new and larger oligomers are formed, preventing irreversible client aggregation and allowing ATP-dependent chaperones recognition to assist protein refolding [6]. HSPBs contribute to protein quality control (PQC) and work to prevent protein aggregation and to generate a pool of non-native proteins that can be rapidly folded [7]. The human genome encodes 10 HSPBs named HSPB1 through HSPB10, with an apparent molecular mass of 12-43 kDa [8]. ...
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... Molecular chaperones, in particular the heat shock proteins (HSPs), are the prime line of defense to counteract protein misfolding and the ensuing protein deposition; they recognize hydrophobic regions of proteins and promote either their refolding or their transfer to the UPS or autophagy systems [230]. The small HSPs are ATPindependent chaperones, a particular class of HSPs that bind misfolded and aggregation-prone proteins, avoiding undesired intermolecular interactions and preventing their aggregation with ensuing loss of function [231,232]. The UPS is localized both in the cytoplasm and in the nuclei; it provides rapid degradation of proteins following their polyubiquitination and subsequent delivery to the proteasome. ...
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