Chaperone-mediated autophagy in health and disease

Abstract

Chaperone-mediated autophagy (CMA) is a lysosomal pathway that participates in the degradation of cytosolic proteins. CMA is activated by starvation and in response to stressors that result in protein damage. The selectivity intrinsic to CMA allows for removal of damaged proteins without disturbing nearby functional ones. CMA works in a coordinated manner with other autophagic pathways, which can compensate for each other. Interest in CMA has recently grown because of the connections established between this autophagic pathway and human pathologies. Here we review the unique properties of CMA compared to other autophagic pathways and its relevance in health and disease.

Figure 1. Chaperone-mediated autophagy, basic components and regulation. (a) Steps on CMA

The two essential components of CMA are the cargo recognition complex (in the cytosol) and the cargo translocation complex (at the lysosomal membrane). The CMA targeting motif (KFERQ-like) in the substrate protein is recognized by cytosolic hsc70, main component of the cargo recognition complex, and this delivers it to the surface of the lysosomes where it binds to LAMP-2A. This single span membrane protein and a luminal form of hsc70 (lys-hsc70) are the major components of the cargo translocation complex. Whereas substrate proteins bind to monomeric forms of LAMP-2A, organization of LAMP-2A into high order multimeric complexes is required for substrate translocation. Once in the lumen the substrate is rapidly degraded. (b–c) Regulation of CMA. CMA activity is directly dependent on the amount of LAMP-2A molecules available at the lysosomal membrane. Levels of LAMP-2A are regulated by de novo synthesis (not depicted here), through changes in their regulated Cathepsin A-dependent degradation at the lysosomal membrane (b) and by the direct insertion of a luminal resident pool of LAMP-2A into the lysosomal membrane (c).

Figure 2. Contribution of CMA dysfunction to pathogenesis in neurodegeneration

Different pathogenic proteins (α-synuclein and Tau) depicted here, have been shown to have a primary detrimental effect on CMA activity. Whereas wild-type or unmodified forms of these proteins (green circles) can be targeted and taken up by lysosomes via CMA (a), their pathogenic counterparts (brown circles) are delivered to the CMA translocation complex at the lysosomal membrane but fail to translocate into the lumen (b). These pathogenic proteins often organize into irreversible oligomeric complexes at the lysosomal membrane that further block CMA activity. Cells respond to CMA blockage by upregulating macroautophagy, the only proteolytic pathway that can directly degrade proteinaceous inclusions and aggregates (b). Failure of macroautophagy with time – due to exhaustion or primary damage by the pathogenic proteins – could precipitate progression of disease (c).