Chaperone-mediated autophagy: selectivity pays off

Abstract

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.

Figure 1. Hypothetical model of the steps and components of chaperone-mediated autophagy (CMA)

(i) Substrate proteins bearing a targeting motif are recognized by HSC70 and co-chaperones in the cytosol. (ii) The chaperone/substrate protein complex is delivered to the surface of lysosomes where it binds to the cytosolic tail of monomer of LAMP-2A. (iii) Substrate binding drives multimerization of LAMP-2A into a translocation complex. In between this and the next step, the substrate is unfolded by yet unknown mechanisms. (iv) The substrate crosses the lysosomal membrane assisted by a luminal form of HSC70. (v) Once inside the lysosome, the substrate is rapidly degraded (dotted structure). (vi) HSC70 promotes disassembly of LAMP-2A from the translocation unit, now devoid of substrate, to provide monomeric forms of LAMP-2A for a new cycle of substrate binding and translocation.

Figure 2. Regulation of the dynamics of LAMP-2A in lysosomes

(a) Under basal conditions, a percentage of LAMP-2A molecules at the lysosomal membrane are continuously turned over through their recruitment to lipid microdomains (green) where the proteases required for cleavage reside. (b) Activation of CMA is associated with (i) mobilization of LAMP-2A outside of the lipid microdomains to prevent degradation and result in a net increase of LAMP-2A. (ii) LAMP-2A undergoes assembly and disassembly to mediate substrate binding and uptake. Increased LAMP-2A levels can also be attained by (iii) recruiting a percentage of full size LAMP-2A that normally resides in the lysosomal lumen or (iv) through de novo synthesis of LAMP-2A in the ER.

Figure 3. Pathophysiology of CMA

CMA fulfills two general functions shared with other autophagic pathways - providing an alternative source of (a) energy and (b) performing quality control. (c) In addition, some specialized functions have also been proposed for CMA which are often cell type dependent. Some of the physiological consequences of each of those CMA functions (green) and the cellular alterations resulting from CMA dysfunction (red) are summarized.

Figure I of Box 1. Types of autophagy in mammalian cells

Three different main types of autophagy have been described in mammalian cells: (a) Macroautophagy, (b) Microautophagy, and (c) Chaperone-mediated autophagy (CMA).