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. ATG4B is one of four ATG4 homologs (ATG4A, ATG4B, ATG4C, and ATG4D) involved in autophagosome elongation. ATG4B encodes a 48 kDa protein called autophagin-1 that is a member of the C54 family of cysteine proteases. ATG4B exists in an autoinhibited state where two of its structural domains hide its catalytic cysteine (1). ATG4B binding to its substrate induces a conformational change that exposes the active site and allows cleavage of the substrate. ATG4B is the least specific of the ATG4 family and is capable of recognizing multiple homologs of its substrate ATG8 (2).
ATG8 is an ubiquitin-like protein involved in expansion of the phagophore and maturation into an autophagosome. ATG8 is expressed as an inactive protein that must be processed before it is covalently attached to a phosphatidylethanolamine (PE) molecule on the surface of an autophagosome (3). The first step in the post-translational processing of ATG8 is C-terminal cleavage by ATG4B. The activated ATG8 then undergoes a series of enzymatic reactions involving ATG7, ATG2, and the ATG12-ATG5-ATG16 complex before its final conjugation to a PE molecule. ATG8 lipidation is a reversible process such that the ATG8 molecule can be recycled. ATG4B also plays a role in ATG8 recycling by cleaving the amide bond between ATG8 and PE.
Dysregulation of autophagy has been implicated in a number of pathological conditions. Mutations in ATG4 proteases are linked to Crohn’s disease and Inflammatory Bowel disease (3). The ATG4 homologs have also been implicated in the pathogenesis of HIV, Hepatitis C, and other infectious diseases. Overexpression of ATG4B is linked to aberrant mTOR signaling and tumor proliferation in colorectal cancer, suggesting a role for ATG4B as a prognostic factor (4). ATG4B has also been shown to play a role in chemoresistance to chronic myeloid leukemia and prostate cancer therapies (3).While data suggests ATG4B involvement in cancer, there is very little known about its specific role in tumorigenesis. A better understanding of ATG4B signaling is important for optimizing our current therapies as well as developing new ones. All of this evidence supports the need for further research into all of the ATG4 proteases.
Novus Biologicals offers ATG4B reagents for your research needs including:
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