Chaperone-mediated autophagy (CMA)

Chaperone-mediated autophagy is a selective lysosomal protein degradation pathway distinct from macroautophagy and microautophagy. It targets cytosolic proteins containing a KFERQ-like pentapeptide motif. These substrate proteins are recognized by the chaperone Hsc70 and delivered to the lysosome-associated membrane protein type 2A (LAMP2A), which acts as both receptor and translocation channel at the lysosomal membrane. The substrate unfolds before being translocated into the lysosome with assistance from luminal chaperones like Hsc70, where it is degraded by proteases[1][4][5]. CMA plays critical roles in cellular quality control, energy homeostasis through regulated turnover of metabolic enzymes, cell cycle progression, immune function modulation, aging/longevity determination, and adaptation to stressors such as starvation or oxidative damage[4][5][7]. Dysregulation of CMA has been implicated in cancer progression—where upregulated CMA supports tumor survival—and in neurodegenerative diseases—where reduced activity leads to toxic protein accumulation—as well as cardiovascular diseases like atherosclerosis[2][3][6]. While considered an attractive therapeutic target due to its central role in multiple pathologies,[6] "chaperone-mediated autophagy" refers to an entire biological process rather than a discrete molecular entity. Important clarification: "Chaperone-mediated autophagy" describes a cellular process, not an individual molecule/receptor/protein. The actual druggable targets within this pathway are typically specific proteins such as Lysosome-associated membrane protein type 2A (LAMP2A) or Heat shock cognate 71 kDa protein (Hsc70).