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Review
. 2018 Jun;19(6):365-381.
doi: 10.1038/s41580-018-0001-6.

The coming of age of chaperone-mediated autophagy

Susmita Kaushik  1   2 , Ana Maria Cuervo  3   4
Affiliations
Review

The coming of age of chaperone-mediated autophagy

Susmita Kaushik et al. Nat Rev Mol Cell Biol. 2018 Jun.

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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Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Autophagic pathways in mammals.
a Macroautophagy sequesters cytosolic cargo by a delimiting membrane that forms through conjugation of specific proteins among themselves and with lipids in a complex multistep process. The membrane then seals into an autophagosome that is trafficked by microtubules. Fusion of autophagosomes with lysosomes mediates degradation of the trapped cargo. Macroautophagy can be in bulk or selective depending on the cargo sequestered. b Microautophagy entraps cytosolic cargo in small vesicles formed by invagination of the lysosomal membrane either in bulk or selectively via recognition and targeting by heat shock cognate 71 kDa protein (HSC70; also known as HSPA8) and cochaperones that are yet to be determined. c Chaperone-mediated autophagy (CMA) involves the selective degradation of KFERQ-like motif-bearing proteins delivered to the lysosomes via chaperone HSC70 and cochaperones, such as carboxyl terminus of HSC70-interacting protein (CHIP), heat shock protein 40 (HSP40; also known as DNABJ1) and HSP70–HSP90 organizing protein (HOP), and their internalization in lysosomes via the receptor lysosome-associated membrane protein type 2A (LAMP2A). Bottom: evolutionary conservation of each autophagy pathway. CASA, chaperone-assisted selective autophagy; GFAP, glial fibrillary acidic protein; lys-HSC70, lysosomal HSC70; Ub, ubiquitin.
Fig. 2
Fig. 2. Lysosomal effectors and regulators of CMA.
Steps in selective degradation of proteins by chaperone-mediated autophagy (CMA): recognition of the KFERQ-like motif in the substrate by heat shock cognate 71 kDa protein (HSC70; also known as HSPA8) (step 1); binding of the substrate–chaperone complex to lysosome-associated membrane protein type 2A (LAMP2A) (step 2); unfolding of the substrate by the chaperone complex (step 3); formation of the CMA translocation complex (step 4); substrate translocation mediated by lysosomal HSC70 (lys-HSC70) (step 5); substrate degradation by lysosomal proteases (step 6); and dissociation of LAMP2A from the translocation complex (step 7). CMA regulation via cytosolic and lysosomal signalling events is shown. Turnover of LAMP2A occurs in lipid microdomains by the dual action of cathepsin A and a metalloproteinase. Top right: activators and inhibitors of CMA. EF1α, elongation factor 1-α; GFAP, glial fibrillary acidic protein; HSP90, heat shock protein 90; mb-HSC70, membrane-associated HSC70; NFAT1, nuclear factor of activated T cells 1; PHLPP1, PH domain leucine-rich repeat-containing protein phosphatase 1; RAR, retinoic acid receptor; TORC2, TOR complex 2.
Fig. 3
Fig. 3. Main physiological roles of CMA.
In most cells, chaperone-mediated autophagy (CMA) participates in protein quality control by degrading oxidized and damaged proteins under stress conditions and also contributes amino acids through degradation of proteins at advanced times of starvation. In addition, depending on the protein substrate degraded, CMA has a modulatory role in multiple cellular pathways. This CMA-mediated selective remodelling of the proteome has recently demonstrated a role for CMA in modulation of carbohydrate and lipid metabolism, transcriptional programmes, immune responses and the cell cycle. The selective CMA substrates linked to those pathways are shown in blue boxes. GFAP, glial fibrillary acidic protein; HSC70, heat shock cognate 71 kDa protein; HSP90, heat shock protein 90; LAMP2A, lysosome-associated membrane protein type 2A; lys-HSC70, lysosomal HSC70; TCA, tricarboxylic acid.
Fig. 4
Fig. 4. CMA in neurodegeneration and cancer.
Chaperone-mediated autophagy (CMA) malfunctioning has been observed in multiple human disorders. Depicted here are two conditions, neurodegeneration and cancer, for which stronger experimental evidence of CMA involvement has been obtained. In neurodegeneration, pathogenic proteins can exert a toxic effect on CMA directly by disrupting the dynamics of the CMA translocation systems or indirectly by affecting levels of CMA effectors or lysosomal biogenesis. Most studies support that CMA has an anti-oncogenic role in normal untransformed cells and prevents malignant transformation, at least in part, through the mechanisms depicted here. In contrast, CMA has a protumorigenic effect in cancer cells by favouring their replication and growth and protecting them from extracellular insults. GFAP, glial fibrillary acidic protein; HSC70, heat shock cognate 71 kDa protein (also known as HSPA8); HSP90, heat shock protein 90; LAMP2A, lysosome-associated membrane protein type 2A; lys-HSC70, lysosomal HSC70.
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