Atg4

Atg4, or autophagy-related gene 4, refers to a family of cysteine proteases central to autophagy. In yeast, Atg4 processes the Atg8 family proteins by cleaving their C-terminus to expose a glycine residue, a prerequisite for conjugation to phosphatidylethanolamine (PE) that anchors Atg8 to autophagic membranes.

Mammals encode multiple Atg4 paralogs (ATG4A, ATG4B, ATG4C, ATG4D), each capable of processing several Atg8-family members including LC3, GATE-16, and the GABARAP subfamily, with varying efficiency. The Atg4 proteases also mediate delipidation, removing Atg8 from PE to recycle Atg8 and regulate autophagosome maturation. Hence, Atg4 has dual roles: activation of Atg8 through processing and later retrieval via deconjugation.

Atg4 activity is coordinated with the Atg7 (E1-like) and Atg3 (E2-like) enzymes that drive Atg8 lipidation. Structural studies show Atg4 contains a catalytic cysteine protease domain; its activity is regulated by redox state and by interactions with Atg8 family members and regulatory proteins. In yeast, Atg4 is a single gene product, whereas higher eukaryotes possess multiple ATG4 genes, contributing to tissue- and context-specific autophagy regulation.

Functionally, Atg4's processing step is essential for autophagy initiation, cargo recognition, and autophagosome formation. Its delipidation function is important for recycling Atg8 and maintaining proper autophagosome size and number. Dysregulation of ATG4 activity has been implicated in disease contexts where autophagy is disrupted, including cancer and neurodegenerative disorders, making ATG4 a focus of autophagy research and therapeutic exploration.