Chaperone-mediated autophagy (CMA)

Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway in which individual cytosolic proteins carrying a KFERQ-like pentapeptide motif (a biochemical recognition sequence defined by charge pattern rather than exact sequence) are delivered directly to the lysosomal lumen without prior vesicle formation. Recognition begins when the constitutively expressed chaperone HSC70 (heat shock cognate 70 kDa protein, encoded by HSPA8) binds the substrate's KFERQ motif in concert with co-chaperones; the complex then docks at the lysosomal membrane via LAMP2A (lysosome-associated membrane protein type 2A), the sole receptor sufficient for CMA translocation, which oligomerizes transiently to form a translocation channel. With advancing age, LAMP2A levels at the lysosomal membrane fall — linked to altered lysosomal lipid composition that accelerates LAMP2A degradation — reducing CMA throughput and allowing damaged or aggregation-prone proteins to accumulate. Zhang and Cuervo (2008) showed in aged rodents that transgenic maintenance of hepatic LAMP2A levels restored CMA activity, improved intracellular protein quality control, and preserved liver metabolic function, providing causal evidence that CMA decline contributes to age-related proteostasis loss. Evidence for age-related CMA decline is strongest in liver and neurons in rodent models; direct human aging data remain limited, and a 2024 review by Endicott noted that the magnitude and universality of decline are tissue- and genetic-background-dependent, warranting caution before extrapolating findings across species or cell types.