Chaperonemediated

Chaperonemediated describes cellular pathways that rely on molecular chaperones to guide proteins through folding, quality control, trafficking, or degradation. The most widely studied example is chaperone-mediated autophagy (CMA), a selective lysosomal degradation pathway for soluble cytosolic proteins.

In CMA, substrate proteins bearing a motif similar to KFERQ are recognized by the cytosolic chaperone HSC70 (HSPA8) and its co-chaperones. The chaperone–substrate complex is delivered to the lysosome, where the receptor LAMP-2A binds the substrate. The protein is unfolded and translocated across the lysosomal membrane, with assistance from lysosome-associated HSP90 and other components. Inside the lysosome, the substrate is degraded by lysosomal proteases.

CMA is substrate-selective rather than a bulk degradation pathway and is tightly regulated by cellular conditions. It is upregulated in response to certain stresses, including oxidative stress and nutrient deprivation, and depends on the abundance and organization of LAMP-2A at the lysosomal membrane. CMA activity tends to decline with aging and can be impaired in various diseases.

Physiological roles of CMA include protein quality control, regulation of metabolism and signaling, and the removal of damaged or modified proteins. Dysregulation or impairment of CMA has been linked to neurodegenerative disorders, cancer, and other aging-related conditions. Beyond CMA, chaperonemediated processes also encompass general chaperone-assisted protein folding and trafficking, where molecular chaperones such as HSP70 and HSP90 families facilitate proper folding and assembly of client proteins.

In summary, chaperonemediated refers to pathways that rely on molecular chaperones to manage protein fate, with CMA representing the most characterized example.