Chaperone-mediated autophagy machinery (CMA) (CMA)

Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway that targets specific cytosolic proteins containing a KFERQ-like pentapeptide motif (Kaushik & Cuervo, 2018). Unlike other forms of autophagy, CMA does not require vesicle formation; instead, the heat shock cognate protein 70 (Hsc70/HSPA8) recognizes the substrate and delivers it to the lysosomal membrane (Arias & Cuervo, 2011). There, the substrate binds to the Lysosome-associated membrane protein 2A (LAMP2A), which acts as the rate-limiting receptor and translocation pore (Cuervo & Dice, 1996). Once unfolded, the substrate is translocated into the lysosomal lumen for degradation by acid hydrolases, contributing to cellular proteostasis and metabolic regulation (Dong et al., 2020). In neurodegenerative diseases, a decline in CMA activity leads to the accumulation of toxic proteins like alpha-synuclein, making CMA activation a therapeutic goal (Alfaro et al., 2018). Conversely, many cancer cells upregulate CMA to survive metabolic stress, suggesting that CMA inhibition could be an effective anti-tumor strategy (Kon et al., 2011).

Other names

CMAChaperone-dependent autophagyLAMP2A-mediated autophagySelective lysosomal proteolysis

Pharmacological modulation of CMA typically involves the stabilization or transcriptional upregulation of the LAMP2A receptor to increase substrate translocation, or the use of small molecules to interfere with the Hsc70-substrate-LAMP2A interaction (Dong et al., 2020; Kaushik & Cuervo, 2018).