These functions are often linked to the degradation of particular proteins, such as endogenous proteins for antigen presentation, degradation of the neuronal survival factor MEF2D for neuronal homeostasis, of Pax-2 for kidney growth control, or of IκBα for transcriptional modulation in response to stress. CMA is activated as part of the cellular response to stress to eliminate damaged proteins or during prolonged starvation, when it contributes amino acids for the synthesis of essential proteins. Besides the increase in LAMP-2A levels, multimerization of LAMP-2A (that only occurs outside the lipid microdomains) is also required to enhance the activity of this pathway ( d). Bottom: CMA Regulation: Levels of LAMP-2A at the lysosomal membrane are regulated in part by de novo synthesis ( a), by changes in its regulated degradation in discrete lipid microdomains by cathepsin A (Cath A) ( b), and by its insertion/deinsertion from the lysosomal lumen into the membrane ( c). Right after the substrate has crossed the lysosomal membrane, the same chaperone disassembles LAMP-2A from the translocation complex ( 4), allowing for new cycles of binding and uptake ( 5). Chaperones in the lumenal side of the membrane help stabilize LAMP-2A and mediate substrate translocation. At the membrane, substrate proteins bind to monomeric forms of LAMP-2A ( 2) and drive their multimerization into a higher order complex required for substrate translocation ( 3). Top: Steps of CMA: Substrate proteins for CMA bear a targeting motif that, when recognized by a cytosolic chaperone complex ( 1), delivers them to lysosomes.

Chaperone mediated autophagy