Chaperone-mediated autophagy

Chaperone-mediated autophagy (CMA) refers to the chaperone-dependent selection of soluble cytosolic proteins that are then targeted to lysosomes and directly translocated across the lysosome membrane for degradation. The unique features of this type of autophagy are the selectivity on the proteins that are degraded by this pathway and the direct shuttling of these proteins across the lysosomal membrane without the requirement for the formation of additional vesicles (Figure 1).

The proteins that are degraded through CMA are cytosolic proteins or proteins from other compartments once they reach the cytosol. Therefore, some of the components that participate in CMA are present in the cytosol while others are located at the lysosomal membrane (Table I).

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. 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. This substrate protein-chaperone complex binds to lysosome-associated membrane protein type 2A (LAMP-2A), which acts as the receptor for this pathway. LAMP-2A a single span membrane protein, is one of the three spliced variants of a single gene lamp2. The other two isoforms LAMP-2B and LAMP-2C are involved in macroautophagy and vesicular trafficking, respectively. Substrate proteins undergo unfolding after binding to LAMP-2A in a process likely mediated by the membrane associated hsc70 and its co-chaperones Bag1, hip, hop and hsp40, also detected at the lysosomal membrane. This binding of substrates to monomers of LAMP-2A triggers the assembly of LAMP-2A multimers that act as the active translocation complex through which the substrates can pass through after unfolding. Substrate translocation requires the presence of hsc70 inside the lysosomal lumen, which may act by either pulling substrates into the lysosomes or preventing their return to the cytosol. After translocation the substrate proteins are rapidly degraded by the lysosomal proteases. Figure 1 depicts the different steps of CMA.

The limiting step for CMA is the binding of the substrate proteins to LAMP-2A and, consequently, levels of LAMP-2A at the lysosomal membrane correlate directly with CMA activity. Therefore, to modulate the activity of this autophagic pathway, the cell stringently regulates the levels of the CMA receptor at the lysosomal membrane by controlling the degradation rates of LAMP-2A monomers in lysosomes and by de novo synthesis of LAMP-2A molecules. In addition, transport of substrates also depends on the efficiency of the assembly of LAMP-2A into the translocation complex.

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