Lysosome membrane lipid microdomains: novel regulators of chaperone-mediated autophagy

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Abstract
Chaperone‐mediated autophagy (CMA) is a selective mechanism for the degradation of soluble cytosolic proteins in lysosomes. The limiting step of this type of autophagy is the binding of substrates to the lysosome‐associated membrane protein type 2A (LAMP‐2A). In this work, we identify a dynamic subcompartmentalization of LAMP‐2A in the lysosomal membrane, which underlies the molecular basis for the regulation of LAMP‐2A function in CMA. A percentage of LAMP‐2A localizes in discrete lysosomal membrane regions during resting conditions, but it exits these regions during CMA activation. Disruption of these regions by cholesterol‐depleting agents or expression of a mutant LAMP‐2A excluded from these regions enhances CMA activity, whereas loading of lysosomes with cholesterol significantly reduces CMA. Organization of LAMP‐2A into multimeric complexes, required for translocation of substrates into lysosomes via CMA, only occurs outside the lipid‐enriched membrane microdomains, whereas the LAMP‐2A located within these regions is susceptible to proteolytic cleavage and degradation. Our results support that changes in the dynamic distribution of LAMP‐2A into and out of discrete microdomains of the lysosomal membrane contribute to regulate CMA.