Chaperone-mediated autophagy: molecular mechanisms and physiological relevance

Abstract

Chaperone-mediated autophagy (CMA) is a selective lysosomal pathway for the degradation of cytosolic proteins. We review in this work some of the recent findings on this pathway regarding the molecular mechanisms that contribute to substrate targeting, binding and translocation across the lysosomal membrane. We have placed particular emphasis on the critical role that changes in the lipid composition of the lysosomal membrane play in the regulation of CMA, as well as the modulatory effect of other novel CMA components. In the second part of this review, we describe the physiological relevance of CMA and its role as one of the cellular mechanisms involved in the response to stress. Changes with age in CMA activity and the contribution of failure of CMA to the phenotype of aging and to the pathogenesis of several age-related pathologies are also described.

Figure 1. Schematic representation of the steps and regulatory mechanisms of CMA

Top: Steps of CMA: Substrate proteins for CMA bear a targeting motif that, when recognized by a cytosolic chaperone complex (1), delivers them to lysosomes. At the membrane, substrate proteins bind to monomeric forms of LAMP-2A (2) and drive their multimerization into a higher order complex required for substrate translocation (3). Chaperones in the lumenal side of the membrane help stabilize LAMP-2A and mediate substrate translocation. Right after the substrate has crossed the lysosomal membrane, the same chaperone disassembles LAMP-2A from the translocation complex (4), allowing for new cycles of binding and uptake (5). Bottom: CMA Regulation: Levels of LAMP-2A at the lysosomal membrane are regulated in part by de novo synthesis (a), by changes in its regulated degradation in discrete lipid microdomains by cathepsin A (Cath A) (b), and by its insertion/deinsertion from the lysosomal lumen into the membrane (c). Besides the increase in LAMP-2A levels, multimerization of LAMP-2A (that only occurs outside the lipid microdomains) is also required to enhance the activity of this pathway (d).

Figure 2. Pathophysiology of CMA

This model depicts: A. Common functions of CMA in all cells. CMA is activated as part of the cellular response to stress to eliminate damaged proteins or during prolonged starvation, when it contributes amino acids for the synthesis of essential proteins. B. Specific functions of CMA. These functions are often linked to the degradation of particular proteins, such as endogenous proteins for antigen presentation, degradation of the neuronal survival factor MEF2D for neuronal homeostasis, of Pax-2 for kidney growth control, or of IκBα for transcriptional modulation in response to stress. C. Pathologies linked to CMA malfunctioning and the pathogenic proteins degraded by CMA and, where indicated, those responsible for CMA blockage. Abbreviations: aa, amino acids; MEF2D, myocyte enhancer factor 2D; Pax-2, paired box-related transcription factor; IκBα, inhibitor of kappa B; α-syn, α-synuclein; UCHL-1, ubiquitin carboxyl-terminal esterase L1; RCAN1, regulator of calcineurin 1; Htt, huntingtin; Cath A, cathepsin A; TRPML1, transient receptor potential mucolipin-1.