When nutrient supply is limited, the cells respond by activating autophagy, in order to degrade intracellular components to provide energy and building blocks, which the cell can utilize in this dire state. However, it is maximally activated in response to stressors and changes in the cellular nutritional status. ĬMA is active at all times in different tissues (liver, kidney, brain), and almost all cell types in culture studied. 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.ĬMA contributes to the maintenance of cellular homeostasis by facilitating recycling of amino acids of the degraded proteins (contribution to energetic cellular balance) and by eliminating abnormal or damaged proteins (contribution to cellular quality control). Degradation of LAMP-2A monomers at the lysosomal membrane occurs in discrete cholesterol-rich lipid microdomains of the lysosomal membrane and it is mediated by Cathepsin A and an unidentified lysosomal metalloprotease. Īssembly and disassembly of CMA translocation complex is mediated by hsp90 and hsc70 chaperones, respectively. In addition, transport of substrates also depends on the efficiency of the assembly of LAMP-2A into the translocation complex. 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. 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. Figure 1 depicts the different steps of CMA. After translocation the substrate proteins are rapidly degraded by the lysosomal proteases. 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. For instance, research with artificial CMA substrate showed that hsc70 chaperone binding to substrate or lysosomal binding does not necessarily require the substrate protein to be capable of unfolding, however, lysosomal translocation makes unfolding as a necessary criteria for it to be internalized. Here, the translocation complex chooses only the substrate proteins which can unfold for internalization by the lysosomes. 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 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. The other two isoforms LAMP-2B and LAMP-2C are involved in macroautophagy and vesicular trafficking, respectively. LAMP-2A a single span membrane protein, is one of the three spliced variants of a single gene lamp2. This substrate protein-chaperone complex binds to lysosome-associated membrane protein type 2A (LAMP-2A), which acts as the receptor for this pathway. 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. 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. Although hsc70 targets cytosolic protein to CMA based on specific amino acid sequence recognition, it works differently when targeting proteins to macro or microautophagy. Specific selection of proteins for degradation in all forms of autophagy came to further understanding as studies discovered the role of chaperones like hsc70. Therefore, some of the components that participate in CMA are present in the cytosol while others are located at the lysosomal membrane ( Table I). The proteins that are degraded through CMA are cytosolic proteins or proteins from other compartments once they reach the cytosol. 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). 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.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |