Chaperone-mediated autophagy

Specific selection of proteins for degradation in all forms of autophagy came to further understanding as studies discovered the role of chaperones like hsc70.[3] In one mechanism for a protein to be a CMA substrate, it must have in its amino acid sequence a pentapeptide motif biochemically related to KFERQ.[4] This CMA-targeting motif is recognized by a cytosolic chaperone, heat shock cognate protein of 70 kDa (hsc70) which targets the substrate to the lysosome surface.[5] This substrate protein-chaperone complex binds to lysosome-associated membrane protein type 2A (LAMP-2A), which acts as the receptor for this pathway.[11] Therefore, assembly, disassembly of LAMP-2A into active translocation complex, and its degradation in microdomain regions, highlights the dynamic nature of this process and the importance of lateral mobility of the CMA receptor at the lysosomal membrane.[12] CMA is active at all times in different tissues (liver, kidney, brain), and almost all cell types in culture studied.[21] CMA performs various specialized functions as well, depending on the specific protein undergoing degradation through this pathway and the cell type involved.Studies in a transgenic mouse model in which normal levels of LAMP-2A are maintained throughout life, showed that these animals had ‘cleaner’ cells, better response to stress – and overall, a better health-span.[30] These studies support the possible contribution of declined CMA activity to poor cellular homeostasis and inefficient response to stress characteristic of old organisms.[37][38] In these cases, the defect lies in the ‘tight’ binding to the lysosomal membrane of pathogenic proteins known to accumulate in these disorders (α-synuclein, UCHL1 in Parkinson’s disease and mutant Tau in tauopathies).