Figure 2.

Molecular partner-mediated lipophagy pathway. Under stress conditions, the KFERQ domains on PLIN2 and PLIN3 are recognized by HSC70, forming substrate–chaperone complexes. These complexes bind to LAMP2A on the lysosomal membrane, where the chaperone complex alters the conformation of the substrate, forming CMA translocation complexes. Subsequently, lys-HSC70 mediates substrate translocation, promoting the degradation of PLIN2 and PLIN3 by lysosomal proteases. Losing the protection of PLIN2 and PLIN3 makes the neutral lipids in the lipid droplets more susceptible to being accessed by cytoplasmic ATGL or phagocytic vesicles, triggering subsequent lipolysis or lipophagy.