Autophagy - Process and Pathways

Process and Pathways

There are three main pathways involved in autophagy and these are mediated by the autophagy-related genes and their associated proteases.

Macroautophagy is the main pathway, occurring mainly to eradicate damaged cell organelles or unused proteins. This involves the formation of a double membrane around the organelle known as an autophagosome. This formation is induced by class 3 phosphoinositide-3-kinase, the autophagy-related gene (Atg) 6 (also known as Beclin-1) and ubiquitin complexes. Other proteases such as Atg4, Atg12, Atg5, and Atg16 are also involved in the regulation of these pathways. The autophagosome travels through the cytoplasm of the cell to a lysosome, and the two membranes fuse together allowing the autophagosome to enter via endocytosis. Within the lysosome, the contents of the autophagosome are degraded via acidic lysosomal hydrolases.

Microautophagy, on the other hand, involves the direct engulfment of cytoplasmic material into the lysosome. This occurs by invagination, meaning the inward folding of the lysosomal membrane, or cellular protrusion.

Chaperone-mediated autophagy, or CMA, is a very complex and specific pathway, which involves the recognition of the hsc70-containing receptor. This means that a protein must contain the recognition site for this hsc70 complex which will allow it to bind to the enzyme, forming the CMA- substrate/chaperone complex. This complex then moves to the lysosomal membrane-bound protein that will recognise and bind with the CMA complex, allowing it to enter the cell. Upon recognition, the enzyme complex begins to break down the protein and it is translocated across the lysosome membrane with the assistance of the lysosomal hsc70 receptor. CMA is significantly different from other types of autophagy because it translocates protein material in a one by one manner, and it is extremely selective about what material crosses the lysosomal barrier.