Atg12

ATG12 is a small ubiquitin-like protein that participates in autophagy, a cellular pathway that degrades and recycles cytoplasmic components through autophagosomes. In mammals and most eukaryotes, ATG12 is encoded by the ATG12 gene and is produced as a precursor that is cleaved by the cysteine protease ATG4 to expose a C-terminal glycine, which is essential for its conjugation reactions.

In a ubiquitin-like conjugation cascade, ATG12 is activated by the E1-like enzyme ATG7, transferred to the E2-like enzyme ATG10, and then covalently conjugated to the lysine residue of ATG5. The resulting ATG12–ATG5 conjugate associates with ATG16L1 to form a multimeric complex that localizes to the expanding phagophore, the precursor to the autophagosome. This complex functions as an E3-like facilitator that promotes the lipidation of LC3, a key step in autophagosome maturation. LC3 is processed to LC3-I, activated by ATG7, transferred to ATG3, and conjugated to phosphatidylethanolamine to form LC3-II on autophagosomal membranes; the ATG12–ATG5–ATG16L1 complex enhances this lipidation process.

ATG12 is essential for autophagosome formation and efficient autophagy. It participates in various selective autophagy pathways, including mitophagy, xenophagy, and aggrephagy, and contributes to cellular homeostasis, immune responses, and development. Dysregulation of ATG12-dependent autophagy has been linked to altered cellular stress responses in experimental models and may influence disease processes in a context-dependent manner.