Chaperone-mediated autophagy in protein quality control

Abstract

Chaperone-mediated autophagy is a selective mechanism for degradation of soluble cytosolic proteins in lysosomes that distinguishes itself from other autophagic pathways by the selectivity with which CMA substrates are targeted for degradation. The recent molecular dissection of this autophagic pathway and the development of experimental models with compromised CMA have unveiled the important contribution of this pathway to protein quality control. In fact, CMA activation seems to be a common mechanism of cellular defense against proteotoxicity.

Figure 1. Molecular components of chaperone-mediated autophagy

Scheme of the sequential steps that mediate degradation of cytosolic proteins through chaperone-mediated autophagy (CMA): 1. Recognition of cytosolic proteins by hsc70 and its co-chaperones. 2. Binding of the chaperone/substrate complex to the receptor at the lysosomal membrane. 3. Unfolding of the substrate protein. 4. Translocation across the lysosomal membrane. 5. Degradation in the lysosomal lumen. Insets: A. Regulation of the stability of the CMA translocation complex B. Dynamics of the CMA receptor at the lysosomal membrane. .

Figure 2. CMA dysfunction in protein conformational disorders

CMA contributes to protein quality control and maintenance of the stability of the proteome. Consequently, alterations in this autophagic pathway have been linked to different protein conformational disorders. This scheme displays some of these disorders in kidney and in the central nervous system, and illustrates the potential negative effect that changes with age in CMA activity have in the progression of these diseases.