Chaperone-mediated autophagy (CMA) was the first studied process that indicated that degradation of intracellular components by the lysosome can be selective - a concept that is now well accepted for ...other forms of autophagy. Lysosomes can degrade cellular cytosol in a nonspecific manner but can also discriminate what to target for degradation with the involvement of a degradation tag, a chaperone and a sophisticated mechanism to make the selected proteins cross the lysosomal membrane through a dedicated translocation complex. Recent studies modulating CMA activity in vivo using transgenic mouse models have demonstrated that selectivity confers on CMA the ability to participate in the regulation of multiple cellular functions. Timely degradation of specific cellular proteins by CMA modulates, for example, glucose and lipid metabolism, DNA repair, cellular reprograming and the cellular response to stress. These findings expand the physiological relevance of CMA beyond its originally identified role in protein quality control and reveal that CMA failure with age may aggravate diseases, such as ageing-associated neurodegeneration and cancer.
A variety of mechanisms deliver cytosolic materials to the lysosomal compartment for degradation through autophagy. Here, we focus on two autophagic pathways, the chaperone-mediated autophagy and the ...endosomal microautophagy that rely on the cytosolic chaperone hsc70 for substrate targeting. Although hsc70 participates in the triage of proteins for degradation by different proteolytic systems, the common characteristic shared by these two forms of autophagy is that hsc70 binds directly to a specific five-amino acid motif in the cargo protein for its autophagic targeting. We summarize the current understanding of the molecular machineries behind each of these types of autophagy.
Chaperone-mediated autophagy (CMA) selectively degrades a subset of cytosolic proteins in lysosomes. A potent physiological activator of CMA is nutrient deprivation, a condition in which ...intracellular triglyceride stores or lipid droplets (LDs) also undergo hydrolysis (lipolysis) to generate free fatty acids for energetic purposes. Here we report that the LD-associated proteins perilipin 2 (PLIN2) and perilipin 3 (PLIN3) are CMA substrates and their degradation through CMA precedes lipolysis. In vivo studies revealed that CMA degradation of PLIN2 and PLIN3 was enhanced during starvation, concurrent with elevated levels of cytosolic adipose triglyceride lipase (ATGL) and macroautophagy proteins on LDs. CMA blockage both in cultured cells and mouse liver or expression of CMA-resistant PLINs leads to reduced association of ATGL and macrolipophagy-related proteins with LDs and the subsequent decrease in lipid oxidation and accumulation of LDs. We propose a role for CMA in LD biology and in the maintenance of lipid homeostasis.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
This review focuses on chaperone-mediated autophagy （CMA）, one of the proteolytic systems that contributes to degradation of intracellular proteins in lysosomes. CMA substrate proteins are ...selectively targeted to lysosomes and translocated into the lysosomal lumen through the coordinated action of chaperones located at both sides of the membrane and a dedicated protein translocation complex. The selectivity of CMA permits timed degradation of spe- cific proteins with regulatory purposes supporting a modulatory role for CMA in enzymatic metabolic processes and subsets of the cellular transcriptional program. In addition, CMA contributes to cellular quality control through the removal of damaged or malfunctioning proteins. Here, we describe recent advances in the understanding of the molecular dynamics, regulation and physiology of CMA, and discuss the evidence in support of the contribution of CMA dysfunction to severe human disorders such as neurodegeneration and cancer.
All cellular proteins undergo continuous synthesis and degradation. This permanent renewal is necessary to maintain a functional proteome and to allow rapid changes in levels of specific proteins ...with regulatory purposes. Although for a long time lysosomes were considered unable to contribute to the selective degradation of individual proteins, the discovery of chaperone-mediated autophagy (CMA) changed this notion. Here, we review the characteristics that set CMA apart from other types of lysosomal degradation and the subset of molecules that confer cells the capability to identify individual cytosolic proteins and direct them across the lysosomal membrane for degradation.
Lipids stored in lipid droplets are hydrolyzed via either cytosolic lipases or a selective form of macroautophagy known as lipophagy. We recently demonstrated that chaperone-mediated autophagy (CMA) ...is required for the initiation of lipolysis by either of these independent lipolytic pathways. CMA selectively degrades the lipid droplet proteins perilipins (PLIN) 2 and 3 from the lipid droplet surface, thus, facilitating the recruitment of cytosolic lipases and autophagy effector proteins to the lipid droplets. PLIN2 phosphorylation was observed upon induction of lipolysis, but the phosphorylating kinase and the relation of this phosphorylation with CMA of PLIN2 remained unknown. Here, we report that phosphorylation of PLIN2 is dependent on AMPK and occurs after the interaction of PLIN2 with the CMA chaperone HSPA8/Hsc70. Our results highlight a role for posttranslational modifications in priming proteins to be amenable for degradation by CMA.
Different types of autophagy coexist in most mammalian cells, and each of them fulfills very specific tasks in intracellular degradation. Some of these autophagic pathways contribute to cellular ...metabolism by directly hydrolyzing intracellular lipid stores and glycogen. Chaperone‐mediated autophagy (CMA), in contrast, is a selective form of autophagy that can only target proteins for lysosomal degradation. Consequently, it was expected that the only possible contribution of this pathway to cellular metabolism would be by providing free amino acids resulting from protein breakdown. However, recent studies have demonstrated that disturbance in CMA leads to important alterations in glucose and lipid metabolism and in overall organism energetics. Here, we describe the unique mechanisms by which CMA contributes to the regulation of cellular metabolism and discuss the possible implications of these previously unknown functions of CMA for the pathogenesis of common metabolic diseases.
Chaperone‐mediated autophagy (CMA) contributes to metabolic regulation through selective and timely degradation of key metabolic enzymes that participate in glycolysis and lipogenesis. This autophagic pathway also regulates lipolysis by selectively removing perilipins from the surface of lipid droplets. Loss of CMA activity with age and in different pathologies may underlie the basis of the metabolic syndrome associated to these conditions.
Autophagy contributes to cellular quality control and energetics through lysosomal breakdown and recycling of essential cellular components. Chaperone-mediated autophagy (CMA) adds to these ...autophagic functions the ability to timely and selectively degrade single tagged proteins to terminate their cellular function and, in this way, participate in the regulation of multiple cellular processes. Many cancer cells upregulate CMA for protumorigenic and prosurvival purposes. However, growing evidence supports a physiological role for CMA in limiting malignant transformation. Understanding the mechanisms behind this functional switch of CMA from antioncogenic to pro-oncogenic is fundamental for targeting CMA in cancer treatment. We summarize current understanding of CMA functions in cancer biology and discuss the basis for its context-dependent dual role in oncogenesis.
CMA is a component of the proteostasis network for protein quality control, but it has additional regulatory roles by terminating the function of key cellular proteins through their timely and selective degradation.Cells with reduced CMA have a higher facility for malignant transformation, in support of a physiological antioncogenic function of CMA.Multiple types of cancer cells and tumors upregulate CMA, and blockade of CMA reduces their tumorigenic capabilities.Cancer cells depend on CMA for a variety of pro-oncogenic functions such as sustained glycolytic activity, resistance to stressors, and maintenance of high oncogene load.The mechanisms behind the switch between the antioncogenic function of CMA in untransformed cells and its pro-oncogenic function in cancer cells remain poorly understood.
The activity of chaperone-mediated autophagy (CMA), a catabolic pathway for selective degradation of cytosolic proteins in lysosomes, decreases with age, but the consequences of this functional ...decline in vivo remain unknown. In this work, we have generated a conditional knockout mouse to selectively block CMA in liver. We have found that blockage of CMA causes hepatic glycogen depletion and hepatosteatosis. The liver phenotype is accompanied by reduced peripheral adiposity, increased energy expenditure, and altered glucose homeostasis. Comparative lysosomal proteomics revealed that key enzymes in carbohydrate and lipid metabolism are normally degraded by CMA and that impairment of their regulated degradation contributes to the metabolic abnormalities observed in CMA-defective animals. These findings highlight the involvement of CMA in regulating hepatic metabolism and suggest that the age-related decline in CMA may have a negative impact on the energetic balance in old organisms.
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•Blockage of liver CMA leads to hepatosteatosis and altered glucose metabolism•Hepatic CMA failure has a negative impact on the whole-body energetic balance•Metabolic enzymes are a major component of the subproteome degraded by CMA•CMA degradation of metabolic enzymes contributes to regulation of metabolism
Schneider et al. show that loss of LAMP-2A, the limiting component of chaperone-mediated autophagy (CMA), in the liver results in perturbations in hepatic carbohydrate and lipid metabolism. CMA selectively degrades enzymes in carbohydrate and lipid metabolism, and failure of CMA, as occurs with age, may underlie the associated metabolic dysregulation.
Degradation of intracellular components in lysosomes, generically known as autophagy, can occur through different pathways. This review discusses chaperone-mediated autophagy (CMA), a type of ...autophagy set apart from other autophagic pathways owing to its selectivity and distinctive mechanism by which substrates reach the lysosomal lumen. CMA participates in quality control and provides energy to cells under persistently poor nutritional conditions. Alterations in CMA have recently been shown to underlie some severe human disorders for which the decline with age in the activity of this pathway might become a major aggravating factor. Prevention of the age-dependent decline in CMA has major beneficial effects on cellular and organ homeostasis and function, revealing that CMA is an essential component of the anti-aging fight.
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