Chaperone-mediated autophagy: roles in disease and aging

Abstract

This review focuses on chaperone-mediated autophagy (CMA), one of the proteolytic systems that contributes to degradation of intracellular proteins in lysosomes. CMA substrate proteins are selectively targeted to lysosomes and translocated into the lysosomal lumen through the coordinated action of chaperones located at both sides of the membrane and a dedicated protein translocation complex. The selectivity of CMA permits timed degradation of specific proteins with regulatory purposes supporting a modulatory role for CMA in enzymatic metabolic processes and subsets of the cellular transcriptional program. In addition, CMA contributes to cellular quality control through the removal of damaged or malfunctioning proteins. Here, we describe recent advances in the understanding of the molecular dynamics, regulation and physiology of CMA, and discuss the evidence in support of the contribution of CMA dysfunction to severe human disorders such as neurodegeneration and cancer.

Figure 1

Steps and physiological functions of CMA. (A) Proteins degraded by CMA are identified in the cytosol by a chaperone complex that, upon binding to the targeting motif in the substrate protein (1), brings it to the surface of lysosomes (2). Binding of the substrate to the cytosolic tail of the receptor protein LAMP-2A promotes LAMP-2A multimerization to form a translocation complex (3). Upon unfolding, sustrate proteins cross the lysosomal membrane (4) assisted by a luminal chaperone and reach the lysosomal matrix where they undergo complete degradation (5). (B) General and cell-type specific functions of CMA and consequences of CMA failure in different organs and systems.

Figure 2

Impairment of CMA by pathogenic proteins contributes to neurodegeneration. (A) Mechanisms of CMA failure in Parkinson's disease (PD). Many PD-related proteins bear CMA-targeting motifs (α-synuclein, UCH-LI and LRRK2 shown here) (top). LRRK2 has eight CMA-targeting motifs but only the sequence of the most commonly used is shown. Both wild-type α-synuclein and LRRK2 are degraded by CMA. Mutant forms of these proteins and of UCH-L1 bind abnormally to LAMP-2A, albeit via different mechanisms, leading to blockage of their own degradation as well as degradation of other CMA substrates. Dopamine-modified α-synuclein and abnormally high levels of wild-type LRRK2 also impair CMA. Failure of CMA causes accumulation and aggregation of these toxic proteins that could contribute to Lewy body formation in PD. Alterations of CMA by mutant LRRK2 and UCH-L1 show converging toxic effects on α-synuclein aggregation. (B) Perturbation of CMA by mutant tau in tauopathies. wild-type tau protein is a bona fide CMA substrate carrying two CMA-targeting motifs (top). Pathogenic variants of tau fail to translocate fully into the lysosomal lumen. Such inefficient translocation promotes partial cleavage of tau and formation of tau oligomers at the lysosomal membrane resulting in destabilization of lysosomal membrane and lysosomal leakage. Release of lysosomal tau oligomers into the cytosol may act as a precursor for further tau aggregation.

Figure 3

Cross talk between different proteolytic systems. Increasing evidence shows that different proteolytic systems are wired through multi-levels of interactions to maintain cellular homeostasis. Examples of cross talk implicated in neurodegenerative diseases are highlighted in grey boxes. PD, Parkinson's disease; HD, Huntington's disease; SMA, Spinal muscular atrophy.