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New Advance in Chaperone-Mediated Autophagy
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New Advance in Chaperone-Mediated Autophagy

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Autophagy".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 21420

Special Issue Editor

Dr. Takahiro Seki

E-Mail Website
Guest Editor
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 7-2-1 Kamiohno, Himeji 670-8524, Japan
Interests: chaperone-mediated autophagy; microautophagy; exosome; spinocerebellar ataxia; Parkinson's disease

Special Issue Information

Dear Colleagues,

Chaperone-mediated autophagy (CMA) is a selective proteolytic pathway in the autophagic lysosomal protein degradation system. Specific motifs, called KFERQ motifs, of CMA substrate proteins are recognized by heat shock cognate protein 70 (Hsc70), a molecular chaperone. CMA substrates are delivered to a lysosomal CMA receptor, lysosome-associated membrane protein 2A (LAMP2A) and transported to lysosomal lumen via a translocon complex formed by oligomerization of LAMP2A. Since approximately 75 % proteins are reported to have canonical, phosphorylation-generated, or acetylation-generated KFERQ motifs, CMA is considered to be related to the maintenance of intracellular protein homeostasis. Indeed, CMA has been focused as the regulator of physiological functions and disease pathogenesis. In various organs, the lysosomal protein degradation in kidney is mainly mediated by CMA, because macroautophagy is not active in kidney tissues. Regarding to diseases, impairment of CMA participates in the pathogenesis of Parkinson’s disease, because CMA is mainly involved in the degradation of α-synuclein, which is highly accumulated in Lewy bodies found in affected neurons of Parkinson’s disease patients. In addition, Hsc70 and LAMP2A are decreased in lymphocytes and tissues of Parkinson’s disease patients. This special issue focuses on the recent advances on the roles and mechanisms of CMA.

Dr. Takahiro Seki
Guest Editor

Manuscript Submission Information

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Published Papers (6 papers)

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Research

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16 pages, 6289 KiB  
Article
D-Cysteine Activates Chaperone-Mediated Autophagy in Cerebellar Purkinje Cells via the Generation of Hydrogen Sulfide and Nrf2 Activation
by Erika Ueda, Tomoko Ohta, Ayumu Konno, Hirokazu Hirai, Yuki Kurauchi, Hiroshi Katsuki and Takahiro Seki
Cells 2022, 11(7), 1230; https://doi.org/10.3390/cells11071230 - 05 Apr 2022
Viewed by 2497
Abstract
Chaperone-mediated autophagy (CMA) is a pathway in the autophagy-lysosome protein degradation system. CMA impairment has been implicated to play a role in spinocerebellar ataxia (SCA) pathogenesis. D-cysteine is metabolized by D-amino acid oxidase (DAO), leading to hydrogen sulfide generation in the cerebellum. Although [...] Read more.
Chaperone-mediated autophagy (CMA) is a pathway in the autophagy-lysosome protein degradation system. CMA impairment has been implicated to play a role in spinocerebellar ataxia (SCA) pathogenesis. D-cysteine is metabolized by D-amino acid oxidase (DAO), leading to hydrogen sulfide generation in the cerebellum. Although D-cysteine alleviates the disease phenotypes in SCA-model mice, it remains unknown how hydrogen sulfide derived from D-cysteine exerts this effect. In the present study, we investigated the effects of D-cysteine and hydrogen sulfide on CMA activity using a CMA activity marker that we have established. D-cysteine activated CMA in Purkinje cells (PCs) of primary cerebellar cultures where DAO was expressed, while it failed to activate CMA in DAO-deficient AD293 cells. In contrast, Na2S, a hydrogen sulfide donor, activated CMA in both PCs and AD293 cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) is known to be activated by hydrogen sulfide and regulate CMA activity. An Nrf2 inhibitor, ML385, prevented CMA activation triggered by D-cysteine and Na2S. Additionally, long-term treatment with D-cysteine increased the amounts of Nrf2 and LAMP2A, a CMA-related protein, in the mouse cerebellum. These findings suggest that hydrogen sulfide derived from D-cysteine enhances CMA activity via Nrf2 activation. Full article
(This article belongs to the Special Issue New Advance in Chaperone-Mediated Autophagy)
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17 pages, 5242 KiB  
Article
Palmitic and Stearic Acids Inhibit Chaperone-Mediated Autophagy (CMA) in POMC-like Neurons In Vitro
by Rodrigo Espinosa, Karla Gutiérrez, Javiera Rios, Fernando Ormeño, Liliana Yantén, Pablo Galaz-Davison, César A. Ramírez-Sarmiento, Valentina Parra, Amelina Albornoz, Iván E. Alfaro, Patricia V. Burgos, Eugenia Morselli, Alfredo Criollo and Mauricio Budini
Cells 2022, 11(6), 920; https://doi.org/10.3390/cells11060920 - 08 Mar 2022
Cited by 2 | Viewed by 3291
Abstract
The intake of food with high levels of saturated fatty acids (SatFAs) is associated with the development of obesity and insulin resistance. SatFAs, such as palmitic (PA) and stearic (SA) acids, have been shown to accumulate in the hypothalamus, causing several pathological consequences. [...] Read more.
The intake of food with high levels of saturated fatty acids (SatFAs) is associated with the development of obesity and insulin resistance. SatFAs, such as palmitic (PA) and stearic (SA) acids, have been shown to accumulate in the hypothalamus, causing several pathological consequences. Autophagy is a lysosomal-degrading pathway that can be divided into macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Previous studies showed that PA impairs macroautophagy function and insulin response in hypothalamic proopiomelanocortin (POMC) neurons. Here, we show in vitro that the exposure of POMC neurons to PA or SA also inhibits CMA, possibly by decreasing the total and lysosomal LAMP2A protein levels. Proteomics of lysosomes from PA- and SA-treated cells showed that the inhibition of CMA could impact vesicle formation and trafficking, mitochondrial components, and insulin response, among others. Finally, we show that CMA activity is important for regulating the insulin response in POMC hypothalamic neurons. These in vitro results demonstrate that CMA is inhibited by PA and SA in POMC-like neurons, giving an overview of the CMA-dependent cellular pathways that could be affected by such inhibition and opening a door for in vivo studies of CMA in the context of the hypothalamus and obesity. Full article
(This article belongs to the Special Issue New Advance in Chaperone-Mediated Autophagy)
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Review

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19 pages, 2082 KiB  
Review
Modulating Chaperone-Mediated Autophagy and Its Clinical Applications in Cancer
by Virginie Hubert, Sebastian Weiss, Andrew Jackson Rees and Renate Kain
Cells 2022, 11(16), 2562; https://doi.org/10.3390/cells11162562 - 17 Aug 2022
Cited by 18 | Viewed by 2978
Abstract
Autophagy is a central mechanism for maintaining cellular homeostasis in health and disease as it provides the critical energy through the breakdown and recycling of cellular components and molecules within lysosomes. One of the three types of autophagy is chaperone-mediated autophagy (CMA), a [...] Read more.
Autophagy is a central mechanism for maintaining cellular homeostasis in health and disease as it provides the critical energy through the breakdown and recycling of cellular components and molecules within lysosomes. One of the three types of autophagy is chaperone-mediated autophagy (CMA), a degradation pathway selective for soluble cytosolic proteins that contain a targeting motif related to KFERQ in their amino acid sequence. This motif marks them as CMA substrate and is, in the initial step of CMA, recognised by the heat shock protein 70 (Hsc70). The protein complex is then targeted to the lysosomal membrane where the interaction with the splice variant A of the lysosomal-associated membrane protein-2 (LAMP-2A) results in its unfolding and translocation into the lysosome for degradation. Altered levels of CMA have been reported in a wide range of pathologies including many cancer types that upregulate CMA as part of the pro-tumorigenic phenotype, while in aging a decline is observed and associated with a decrease of LAMP-2 expression. The potential of altering CMA to modify a physiological or pathological process has been firmly established through genetic manipulation in animals and chemical interference with this pathway. However, its use for therapeutic purposes has remained limited. Compounds used to target and modify CMA have been applied successfully to gain a better understanding of its cellular mechanisms, but they are mostly not specific, also influence other autophagic pathways and are associated with high levels of toxicity. Here, we will focus on the molecular mechanisms involved in CMA regulation as well as on potential ways to intersect them, describe modulators successfully used, their mechanism of action and therapeutic potential. Furthermore, we will discuss the potential benefits and drawbacks of CMA modulation in diseases such as cancer. Full article
(This article belongs to the Special Issue New Advance in Chaperone-Mediated Autophagy)
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17 pages, 1678 KiB  
Review
Diving into the Evolutionary History of HSC70-Linked Selective Autophagy Pathways: Endosomal Microautophagy and Chaperone-Mediated Autophagy
by Simon Schnebert, Maxime Goguet, Emilio J. Vélez, Alexandra Depincé, Florian Beaumatin, Amaury Herpin and Iban Seiliez
Cells 2022, 11(12), 1945; https://doi.org/10.3390/cells11121945 - 16 Jun 2022
Cited by 10 | Viewed by 3946
Abstract
Autophagy is a pleiotropic and evolutionarily conserved process in eukaryotes that encompasses different types of mechanisms by which cells deliver cytoplasmic constituents to the lysosome for degradation. Interestingly, in mammals, two different and specialized autophagic pathways, (i) the chaperone-mediated autophagy (CMA) and (ii) [...] Read more.
Autophagy is a pleiotropic and evolutionarily conserved process in eukaryotes that encompasses different types of mechanisms by which cells deliver cytoplasmic constituents to the lysosome for degradation. Interestingly, in mammals, two different and specialized autophagic pathways, (i) the chaperone-mediated autophagy (CMA) and (ii) the endosomal microautophagy (eMI), both rely on the use of the same cytosolic chaperone HSPA8 (also known as HSC70) for targeting specific substrates to the lysosome. However, this is not true for all organisms, and differences exist between species with respect to the coexistence of these two autophagic routes. In this paper, we present an in-depth analysis of the evolutionary history of the main components of CMA and eMI and discuss how the observed discrepancies between species may contribute to improving our knowledge of these two functions and their interplays. Full article
(This article belongs to the Special Issue New Advance in Chaperone-Mediated Autophagy)
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18 pages, 596 KiB  
Review
Chaperone-Mediated Autophagy in Neurodegenerative Diseases and Acute Neurological Insults in the Central Nervous System
by Haruo Kanno, Kyoichi Handa, Taishi Murakami, Toshimi Aizawa and Hiroshi Ozawa
Cells 2022, 11(7), 1205; https://doi.org/10.3390/cells11071205 - 02 Apr 2022
Cited by 22 | Viewed by 4225
Abstract
Autophagy is an important function that mediates the degradation of intracellular proteins and organelles. Chaperone-mediated autophagy (CMA) degrades selected proteins and has a crucial role in cellular proteostasis under various physiological and pathological conditions. CMA dysfunction leads to the accumulation of toxic protein [...] Read more.
Autophagy is an important function that mediates the degradation of intracellular proteins and organelles. Chaperone-mediated autophagy (CMA) degrades selected proteins and has a crucial role in cellular proteostasis under various physiological and pathological conditions. CMA dysfunction leads to the accumulation of toxic protein aggregates in the central nervous system (CNS) and is involved in the pathogenic process of neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease. Previous studies have suggested that the activation of CMA to degrade aberrant proteins can provide a neuroprotective effect in the CNS. Recent studies have shown that CMA activity is upregulated in damaged neural tissue following acute neurological insults, such as cerebral infarction, traumatic brain injury, and spinal cord injury. It has been also suggested that various protein degradation mechanisms are important for removing toxic aberrant proteins associated with secondary damage after acute neurological insults in the CNS. Therefore, enhancing the CMA pathway may induce neuroprotective effects not only in neurogenerative diseases but also in acute neurological insults. We herein review current knowledge concerning the biological mechanisms involved in CMA and highlight the role of CMA in neurodegenerative diseases and acute neurological insults. We also discuss the possibility of developing CMA-targeted therapeutic strategies for effective treatments. Full article
(This article belongs to the Special Issue New Advance in Chaperone-Mediated Autophagy)
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16 pages, 816 KiB  
Review
New Insights into the Mechanisms of Chaperon-Mediated Autophagy and Implications for Kidney Diseases
by Zhen Yuan, Shuyuan Wang, Xiaoyue Tan and Dekun Wang
Cells 2022, 11(3), 406; https://doi.org/10.3390/cells11030406 - 25 Jan 2022
Cited by 9 | Viewed by 3558
Abstract
Chaperone-mediated autophagy (CMA) is a separate type of lysosomal proteolysis, characterized by its selectivity of substrate proteins and direct translocation into lysosomes. Recent studies have declared the involvement of CMA in a variety of physiologic and pathologic situations involving the kidney, and it [...] Read more.
Chaperone-mediated autophagy (CMA) is a separate type of lysosomal proteolysis, characterized by its selectivity of substrate proteins and direct translocation into lysosomes. Recent studies have declared the involvement of CMA in a variety of physiologic and pathologic situations involving the kidney, and it has emerged as a potential target for the treatment of kidney diseases. The role of CMA in kidney diseases is context-dependent and appears reciprocally with macroautophagy. Among the renal resident cells, the proximal tubule exhibits a high basal level of CMA activity, and restoration of CMA alleviates the aging-related tubular alternations. The level of CMA is up-regulated under conditions of oxidative stress, such as in acute kidney injury, while it is declined in chronic kidney disease and aging-related kidney diseases, leading to the accumulation of oxidized substrates. Suppressed CMA leads to the kidney hypertrophy in diabetes mellitus, and the increase of CMA contributes to the progress and chemoresistance in renal cell carcinoma. With the progress on the understanding of the cellular functions and uncovering the clinical scenario, the application of targeting CMA in the treatment of kidney diseases is expected. Full article
(This article belongs to the Special Issue New Advance in Chaperone-Mediated Autophagy)
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