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The coming of age of chaperone-mediated autophagy

Abstract

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.

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Fig. 1: Autophagic pathways in mammals.
Fig. 2: Lysosomal effectors and regulators of CMA.
Fig. 3: Main physiological roles of CMA.
Fig. 4: CMA in neurodegeneration and cancer.

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S.K. and A.M.C. researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Susmita Kaushik or Ana Maria Cuervo.

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Glossary

Chaperone

A protein that assists during folding of other proteins until they reach their functional conformations. Chaperone substrates include both de novo synthesized native proteins and previously folded proteins that undergo partial unfolding.

Proteostasis networks

Intracellular components, mainly chaperones and proteolytic systems, that control each of the processes that occur from protein synthesis to degradation to prevent protein aggregation and ensure maintenance of a stable proteome.

HIF1α

The hypoxia-inducible factor 1α is a transcription factor that modulates the cellular response to hypoxia. HIF1α orchestrates the transcription of a large set of genes involved in cell proliferation, cell survival, and glucose and iron metabolism.

E3 ubiquitin-protein ligase

Intracellular enzyme that participates in the covalent attachment of ubiquitin moieties to cargo proteins. This tagging is commonly used for the targeting of the protein to the proteasome system for degradation.

MST1

The mammalian STE20-like protein kinase 1 is a protein component of the Hippo signalling pathway that modulates cell proliferation and differentiation.

Cochaperones

Proteins that assist chaperones in their functions by modulating their ATP hydrolytic capability.

HSP90

Heat shock protein 90 is a chaperone that stabilizes proteins in transient conformations and facilitates their final folding. HSP90 often acts in conjunction with other intracellular chaperones such as HSC70.

Lysosome-associated membrane protein

(LAMP). Single-span membrane proteins at the lysosomal membrane with a short C-terminus (12 amino acids) exposed to the cytosol while the rest of the protein is in the lysosomal lumen.

Isoelectric point

The pH at which the net charge on a protein is zero.

Nuclear retinoic acid receptor-α

Nuclear receptor activated by retinoic acid that activates or represses gene expression. Its wide range of targets include genes involved in development, apoptosis, differentiation, autophagy and circadian regulation.

Lipid microdomains

Cholesterol and/or glycosphingolipid-rich regions in membranes that present higher order and density than the surrounding membrane. They can be transient and highly dynamic in terms of resident proteins and lipids and in their size.

Cathepsin

Protease located in the lysosomal lumen that is maximally active at acidic pH.

Cystinosis

Lysosomal storage disorder characterized by the abnormal accumulation of cysteine inside lysosomes owing to a defect in its normal export from this organelle.

Retromer

Multiprotein complex made up of membrane-associated sorting nexin and vacuolar-protein-sorting proteins that recycle transmembrane proteins from endosomes to the Golgi complex and the plasma membrane.

AKT1

Intracellular kinase that participates in signalling pathways that regulate a wide array of intracellular processes, including proliferation, cell survival, metabolism, growth and angiogenesis.

TOR complex 2

(TORC2). One of the two functional multiprotein complexes containing the nutrient sensing kinase TOR. TORC2 plays regulatory roles in actin cytoskeleton dynamics, proliferation, growth and metabolism.

Perilipins

Proteins that cover the surface of lipid droplets and shield the hydrophobic lipid core from the aqueous cytosol. Perilipins also regulate the rate of consumption of the lipids (lipolysis) in the lipid droplet.

Warburg effect

Unique metabolic characteristic of many cancer cells whereby they sustain very high levels of glycolysis followed by lactic acid fermentation rather than the common usage of oxidation of pyruvate in mitochondria that follows glycolysis in most cells.

Immunogenic cell death

Functionally peculiar variant of regulated cell death that — in immunocompetent syngeneic hosts — is sufficient to activate an adaptive immune response against dead cell-associated antigens.

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Kaushik, S., Cuervo, A.M. The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol 19, 365–381 (2018). https://doi.org/10.1038/s41580-018-0001-6

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