There are 3 major autophagy pathways- microautophagy, chaperone-mediated autophagy, and macroautophagy. Macroautophagy is the pathway herein referred to as simply autophagy.
Autophagy can be broken down into 4 main stages: phagophore nucleation, autophagosome elongation, autophagosome docking and fusion with a lysosome, and vesicle breakdown and degradation. ATG4A is one of four human ATG4 homologs (ATG4A, ATG4B, ATG4C, and ATG4D) involved in autophagosome elongation. ATG4A encodes a 45 kDa protein called autophagin-2 that is a member of the C54 family of cysteine proteases. Like ATG4B, ATG4A does not require any cleavage to enable its catalytic activity. ATG4A cleaves the ubiquitin-like protein ATG8 to expose a C-terminal glycine, allowing further post-translational modifications to ATG8. Activated ATG8 is then covalently linked to a phosphatidylethanolamine (PE) molecule on the surface of an autophagosome (1). ATG8 lipidation is an important step in expansion of the phagophore and maturation of the autophagosome.
Humans express 6 ATG8 homologs belonging to two subfamilies (2). The first is the LC3 subfamily comprising LC3A, LC3B, and LC3C. The second is the GABARAP subfamily comprising GABARAP, GATE-16, and ATG8L. While ATG4B has broad specificity for these substrates, ATG4A seems to favor GABARAP and GATE-16. The specificity of the ATG4-ATG8 match may relay different signals for autophagosome formation. Further studies are needed to fully understand the roles and specificities of each ATG4 homolog in autophagy.
Autophagy dysregulation plays an important role in many disease processes. Specifically, derangements in the ATG4 proteases have been identified in intestinal disorders as well as numerous malignancies. In ovarian cancer, hypomethylation of the ATG4A gene promoter correlates with a poor prognosis (3). ATG4A has also been identified to promote tumor stem-cell growth and maintenance in breast cancer cell lines (4). In patients with Crohn’s Disease, ATG4A variants are linked to a more aggressive disease course characterized by extensive inflammation and granuloma formation (5). Further studies of the ATG4 proteases will be important for fully understanding the role of autophagy in these and other disease processes.
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