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Chaperone-mediated autophagy (CMA) is a process triggering the lysosomal-mediated degradation of specific protein targets. CMA is induced by a variety of stresses, including starvation, genotoxic insults, oxidative stress, and hypoxia. CMA upregulation has been linked to the survival and proliferation of cancer cells, while deficiencies in CMA have been described in many neurodegenerative pathologies. The mechanism of CMA is a multi-step process involving substrate recognition, trafficking to the lysosome, and degradation. Substrate recognition involves binding of target proteins containing a penta-peptide KFERQ, or KFERQ-like motif, to the cytosolic chaperone protein heat shock cognate protein 70 (HSC70), also called HSPA8 or HSP73. With the help of additional co-chaperones, including HSP90, HSP40, HOP, HIP, and BAG1, the HSC70-substrate complex is targeted to the lysosomal membrane where it interacts with lysosomal-associated membrane protein 2A (LAMP2A). LAMP2A is one of three splice variants of LAMP2 differing in a small carboxyl-terminal cytoplasmic tail. This region is required for lysosomal docking of HSC70–substrate complexes. Changes in LAMP2A expression through transcriptional regulation or protein stability factor in the regulation of CMA.