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Invaginations of the vacuolar membrane form independently of microtubules. a, in vitro microautophagy reactions were performed in the presence of nocodazole or colchicine and assayed for activity. b, thin section of a BJ3505 cell (pep4; E. Jones, Carnegie Mellon University, Pittsburgh, PA) that had been starved for 3 h in SD-N, quick frozen in liquid propane, freeze-substituted in 0.5% uranyl acetate, and embedded in Lowicryl HM20. The section shows an invagination of the vacuolar membrane () originating far away from the spindle pole body.
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Microautophagy is the transfer of cytosolic components into the lysosome by direct invagination of the lysosomal membrane and subsequent budding of vesicles into the lysosomal lumen. This process is topologically equivalent to membrane invagination during multivesicular body formation and to the budding of enveloped viruses. Vacuoles are lysosomal...
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... 8,11 Chaperone-mediated autophagy (CMA) degrades proteins bearing a pentapeptide KFERQlike motif that, when recognized by the heat-shock cognate protein of 70 kDa (Hsc70), 12 are delivered to lysosomes for binding to the lysosome-associated membrane protein type 2A (LAMP-2A; L2A) 13 and subsequent direct translocation across the membrane for luminal degradation. 14 Microautophagy, originally described in yeast, 15 occurs in mammals via invaginations in the membranes of late endosomes/multivesicular bodies (LE/MVBs) (reviewed in Tekirdag and Cuervo 16,17 and Wang et al. 17 ). In endosomal microautophagy (eMI), 18 the subtype of microautophagy with the highest similarity to CMA, substrates are also targeted for degradation upon recognition of a KFERQ-like motif by Hsc70. ...
Chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI) are pathways for selective degradation of cytosolic proteins in lysosomes and late endosomes, respectively. These autophagic processes share as a first step the recognition of the same five-amino-acid motif in substrate proteins by the Hsc70 chaperone, raising the possibility of coordinated activity of both pathways. In this work, we show the existence of a compensatory relationship between CMA and eMI and identify a role for the chaperone protein Bag6 in triage and internalization of eMI substrates into late endosomes. Association and dynamics of Bag6 at the late endosome membrane change during starvation, a stressor that, contrary to other autophagic pathways, causes a decline in eMI activity. Collectively, these results show a coordinated function of eMI with CMA, identify the interchangeable subproteome degraded by these pathways, and start to elucidate the molecular mechanisms that facilitate the switch between them.
... After fusion, the lysosomal content is degraded by lysosomal hydrolases, and degradation products are released into the cell for re-use (Aman et al., 2021). Microautophagy involves degradation of peroxisomes and mitochondria via invagination of the lysosome membrane (Kunz et al., 2004). In CMA, protein substrates are unfolded by heat shock cognate 71 kDa protein (hsc70) chaperones and translocated across the lysosome membrane via interaction with lysosome-associated membrane protein 2A (LAMP-2A) (Majeski and Fred Dice, 2004). ...
Neurodegenerative diseases are a large class of neurological disorders characterized by progressive dysfunction and death of neurones. Examples include Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Aging is the primary risk factor for neurodegeneration; individuals over 65 are more likely to suffer from a neurodegenerative disease, with prevalence increasing with age. As the population ages, the social and economic burden caused by these diseases will increase. Therefore, new therapies that address both aging and neurodegeneration are imperative. Ketogenic diets (KDs) are low carbohydrate, high-fat diets developed initially as an alternative treatment for epilepsy. The classic ketogenic diet provides energy via long-chain fatty acids (LCFAs); naturally occurring medium chain fatty acids (MCFAs), on the other hand, are the main components of the medium-chain triglyceride (MCT) ketogenic diet. MCT-based diets are more efficient at generating the ketone bodies that are used as a secondary energy source for neurones and astrocytes. However, ketone levels alone do not closely correlate with improved clinical symptoms. Recent findings suggest an alternative mode of action for the MCFAs, e.g., via improving mitochondrial biogenesis and glutamate receptor inhibition. MCFAs have been linked to the treatment of both aging and neurodegenerative disease via their effects on metabolism. Through action on multiple disease-related pathways, MCFAs are emerging as compounds with notable potential to promote healthy aging and ameliorate neurodegeneration. MCFAs have been shown to stimulate autophagy and restore mitochondrial function, which are found to be disrupted in aging and neurodegeneration. This review aims to provide insight into the metabolic benefits of MCFAs in neurodegenerative disease and healthy aging. We will discuss the use of MCFAs to combat dysregulation of autophagy and mitochondrial function in the context of “normal” aging, Parkinson’s disease, amyotrophic lateral sclerosis and Alzheimer’s disease.
... SARS-CoV-2 genome encodes a total of 29 proteins. It synthesizes the polyproteins ORF1a (pp1a) and ORF1b (pp1ab), which will generate the non-structural proteins [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. It also encodes structural proteins that will be part of mature virions, which include the spike (S), envelope (E), membrane (M), and nucleocapsid (N) protein. ...
... The general term of autophagy encompasses three primary types: microautophagy, chaperone-mediated autophagy (CMA), and macroautophagy. Microautophagy involves the direct engulf ment of cytoplasmic material by lysosomes through the invagination of the lysosomal membrane (11). Chaperone-mediated autophagy involves the selective degradation of specific proteins that are recognized by chaperone proteins and delivered to lysosomes through a specific receptor-mediated pathway (12). ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as the causative agent of the recent COVID-19 pandemic, continues representing one of the main health concerns worldwide. Autophagy, in addition to its role in cellular homeostasis and metabolism, plays an important part for the host antiviral immunity. However, viruses including SARS-CoV-2 have evolved diverse mechanisms to not only overcome autophagy's antiviral pressure but also manipulate its machinery in order to enhance viral replication and propagation. Here, we discuss our current knowledge on the impact that autophagy exerts on SARS-CoV-2 replication, as well as the different counteracting measures that this virus has developed to manipulate autophagy's complex machinery. Some of the elements regarding this interplay may become future therapeutic targets in the fight against SARS-CoV-2.
... The non-selective lysosomal degradative process that engulfs cellular components is known as microautophagy [4]. Direct membrane invagination forms vesicles [5] which, in turn, carry cell ingredients to the lysosomal vesicle, starting the breakdown of soluble cytoplasmic components or other completely integrated organelles, such as peroxisomes (Figure 1a). Proteostasis maintenance along with the cellular response to unfavorable situations are both facilitated by CMA [6]. ...
Multiple myeloma (MM) is the second most prevalent hematologic malignancy. In the past few years, the survival of MM patients has increased due to the emergence of novel drugs and combination therapies. Nevertheless, one of the significant obstacles in treating most MM patients is drug resistance, especially for individuals who have experienced relapses or developed resistance to such cutting-edge treatments. One of the critical processes in developing drug resistance in MM is autophagic activity, an intracellular self-digestive process. Several possible strategies of autophagy involvement in the induction of MM-drug resistance have been demonstrated thus far. In multiple myeloma, it has been shown that High mobility group box protein 1 (HMGB1)-dependent autophagy can contribute to drug resistance. Moreover, activation of autophagy via proteasome suppression induces drug resistance. Additionally, the effectiveness of clarithromycin as a supplemental drug in treating MM has been reported recently, in which autophagy blockage is proposed as one of the potential action mechanisms of CAM. Thus, a promising therapeutic approach that targets autophagy to trigger the death of MM cells and improve drug susceptibility could be considered. In this review, autophagy has been addressed as a survival strategy crucial for drug resistance in MM.
... Macroautophagy relies on the cargo being sequestered away from the lysosome/vacuole, in an autophagosome, formed de novo. Microautophagy and CMA both take place directly at the lysosomal membrane-the former requiring invagination of the lysosomal membrane followed by shedding of vesicles into the lumen of the organelle [7] and the latter involving the molecular chaperone complex recognition of a pentapeptide motif, KFERQ, that is present on the surface of a protein destined for degradation followed by its direct transport across the membrane [8]. ...
Cells survey their environment and need to balance growth and anabolism with stress programmes and catabolism towards maximum cellular bioenergetics economy and survival. Nutrient-responsive pathways, such as the mechanistic target of rapamycin (mTOR) interact and cross-talk, continuously, with stress-responsive hubs such as the AMP-activated protein kinase (AMPK) to regulate fundamental cellular processes such as transcription, protein translation, lipid and carbohydrate homeostasis. Especially in nutrient stresses or deprivations, cells tune their metabolism accordingly and, crucially, recycle materials through autophagy mechanisms. It has now become apparent that autophagy is pivotal in lifespan, health and cell survival as it is a gatekeeper of clearing damaged macromolecules and organelles and serving as quality assurance mechanism within cells. Autophagy is hard-wired with energy and nutrient levels as well as with damage-response, and yeasts have been instrumental in elucidating such connectivities. In this review, we briefly outline cross-talks and feedback loops that link growth and stress, mainly, in the fission yeast Schizosaccharomyces pombe, a favourite model in cell and molecular biology.
... Licensing Right NX24OB5K3I, 21 November 2022. During microautophagy, lysosomes take up small cytosolic constituents (soluble or particulate cellular components) by invagination or protrusion of the lysosomal limiting membrane followed by scission [25][26][27][28]. This type of autophagy is non-selective and does not require autophagosome formation. ...
... Genistein (27), a naturally occurring flavonoid, triggers apoptosis in human colon cancer HT-29 cells, mainly via upregulation of CDKN1A/p21 and BAX-BCL2 expression [281]. Moreover, apigenin (26), another flavonoid, triggers caspase-related apoptosis in myeloid leukemia HL60 cells through inhibition of the PI3K-AKT pathway. This effect is celldependent and is not observed in erythroid leukemia TF1 cells. ...
Macroautophagy (autophagy) has been a highly conserved process throughout evolution and allows cells to degrade aggregated/misfolded proteins, dysfunctional or superfluous organelles and damaged macromolecules, in order to recycle them for biosynthetic and/or energetic purposes to preserve cellular homeostasis and health. Changes in autophagy are indeed correlated with several pathological disorders such as neurodegenerative and cardiovascular diseases, infections, cancer and inflammatory diseases. Conversely, autophagy controls both apoptosis and the unfolded protein response (UPR) in the cells. Therefore, any changes in the autophagy pathway will affect both the UPR and apoptosis. Recent evidence has shown that several natural products can modulate (induce or inhibit) the autophagy pathway. Natural products may target different regulatory components of the autophagy pathway, including specific kinases or phosphatases. In this review, we evaluated
~100 natural compounds and plant species and their impact on different types of cancers via the autophagy pathway. We also discuss the impact of these compounds on the UPR and apoptosis via the autophagy pathway. A multitude of preclinical findings have shown the function of botanicals in regulating cell autophagy and its potential impact on cancer therapy; however, the number of related clinical trials to date remains low. In this regard, further pre-clinical and clinical studies are warranted
to better clarify the utility of natural compounds and their modulatory effects on autophagy, as fine-tuning of autophagy could be translated into therapeutic applications for several cancers.
... Licensing Right NX24OB5K3I, 21 November 2022. During microautophagy, lysosomes take up small cytosolic constituents (soluble or particulate cellular components) by invagination or protrusion of the lysosomal limiting membrane followed by scission [25][26][27][28]. This type of autophagy is non-selective and does not require autophagosome formation. ...
... Genistein (27), a naturally occurring flavonoid, triggers apoptosis in human colon cancer HT-29 cells, mainly via upregulation of CDKN1A/p21 and BAX-BCL2 expression [281]. Moreover, apigenin (26), another flavonoid, triggers caspase-related apoptosis in myeloid leukemia HL60 cells through inhibition of the PI3K-AKT pathway. This effect is celldependent and is not observed in erythroid leukemia TF1 cells. ...
Macroautophagy (autophagy) has been a highly conserved process throughout evolution and allows cells to degrade aggregated/misfolded proteins, dysfunctional or superfluous organelles and damaged macromolecules, in order to recycle them for biosynthetic and/or energetic purposes to preserve cellular homeostasis and health. Changes in autophagy are indeed correlated with several pathological disorders such as neurodegenerative and cardiovascular diseases, infections, cancer and inflammatory diseases. Conversely, autophagy controls both apoptosis and the unfolded protein response (UPR) in the cells. Therefore, any changes in the autophagy pathway will affect both the UPR and apoptosis. Recent evidence has shown that several natural products can modulate (induce or inhibit) the autophagy pathway. Natural products may target different regulatory components of the autophagy pathway, including specific kinases or phosphatases. In this review, we evaluated ~100 natural compounds and plant species and their impact on different types of cancers via the autophagy pathway. We also discuss the impact of these compounds on the UPR and apoptosis via the autophagy pathway. A multitude of preclinical findings have shown the function of botanicals in regulating cell autophagy and its potential impact on cancer therapy; however, the number of related clinical trials to date remains low. In this regard, further pre-clinical and clinical studies are warranted to better clarify the utility of natural compounds and their modulatory effects on autophagy, as fine-tuning of autophagy could be translated into therapeutic applications for several cancers.
... In the cooperation of two conserved ubiquitin-like conjugation systems, a portion of cytoplasm, including invasive pathogens, superfluous and damaged organelles, and cytosolic protein aggregates, is enveloped by elongation of PAS, ultimately forming a new vesicle, the autophagosome. Following delivery and fusion with the lysosome, the cargo including contents and its inner membrane is degraded by lysosomal hydrolases, and the breakdown products such as amino acids are released back to the cytoplasm for recycling the macromolecular constituents to reuse as building blocks or a source of energy under unfavorable conditions ( Figure 2) [68]. In addition, ATG proteins are involved in each of these steps and mechanistically regulate the autophagic flux along autophagosome and autophagolysosome biogenesis [25,26,49]. ...
Autophagy is an evolutionally conserved degradation mechanism for maintaining cell homeostasis whereby cytoplasmic components are wrapped in autophagosomes and subsequently delivered to lysosomes for degradation. This process requires the concerted actions of multiple autophagy-related proteins and accessory regulators. In neurons, autophagy is dynamically regulated in different compartments including soma, axons, and dendrites. It determines the turnover of selected materials in a spatiotemporal control manner, which facilitates the formation of specialized neuronal functions. It is not surprising, therefore, that dysfunctional autophagy occurs in epilepsy, mainly caused by an imbalance between excitation and inhibition in the brain. In recent years, much attention has been focused on how autophagy may cause the development of epilepsy. In this article, we overview the historical landmarks and distinct types of autophagy, recent progress in the core machinery and regulation of autophagy, and biological roles of autophagy in homeostatic maintenance of neuronal structures and functions, with a particular focus on synaptic plasticity. We also discuss the relevance of autophagy mechanisms to the pathophysiology of epileptogenesis.
... The concept of microautophagy comes very later after macroautophagy. As such, very less is known about the regulation and mechanism of microautophagy, but using different autophagy inhibitors, the whole process of microautophagy can be divided into four stages as vacuole invagination (stage I), vacuole formation in the lysosome (stage II), uptake of cargo inside the lumen (III), and degradation of the uptake cargo (stage IV) [78]. Microautophagy is an ATP-dependent process where complex molecular machinery is involved in all four stages [88]. ...
Cellular homeostasis is maintained by rapid and systematic cleansing of aberrant and aggregated proteins within cells. Neurodegenerative diseases (NDs) especially Parkinson’s and Alzheimer’s disease are known to be associated with multiple factors, most important being impaired clearance of aggregates, resulting in the accumulation of specific aggregated protein in the brain. Protein quality control (PQC) of proteostasis network comprises proteolytic machineries and chaperones along with their regulators to ensure precise operation and maintenance of proteostasis. Such regulatory factors coordinate among each other multiple functional aspects related to proteins, including their synthesis, folding, transport, and degradation. During aging due to inevitable endogenous and external stresses, sustaining a proteome balance is a challenging task. Such stresses decline the capacity of the proteostasis network compromising the proteome integrity, affecting the fundamental physiological processes including reproductive fitness of the organism. This review focuses on highlighting proteome-wide changes during aging and the strategies for proteostasis improvements. The possibility of augmenting the proteostasis network either via genetic or pharmacological interventions may be a promising strategy towards delaying age-associated pathological consequences due to proteome disbalance, thus promoting healthy aging and prolonged longevity.
... Lastly, stage IV is characterized by its sensitivity to K252a and rapamycin. Nystatin and a temperature of 0 • C directly interfere with phospholipid membrane invagination and scission, while valinomycin and rapamycin disrupt the membrane electrochemical gradient and cell proliferation, respectively [21,22]. ...
Virus-infected cells trigger a robust innate immune response and facilitate virus replication. Here, we review the role of autophagy in virus infection, focusing on both pro-viral and anti-viral host responses using a select group of viruses. Autophagy is a cellular degradation pathway operated at the basal level to maintain homeostasis and is induced by external stimuli for specific functions. The degradative function of autophagy is considered a cellular anti-viral immune response. However, autophagy is a double-edged sword in viral infection; viruses often benefit from it, and the infected cells can also use it to inhibit viral replication. In addition to viral regulation, autophagy pathway proteins also function in autophagy-independent manners to regulate immune responses. Since viruses have co-evolved with hosts, they have developed ways to evade the anti-viral autophagic responses of the cells. Some of these mechanisms are also covered in our review. Lastly, we conclude with the thought that autophagy can be targeted for therapeutic interventions against viral diseases.
