Keeping up with ATG7: conserved functions in Atg8ylation and beyond

Atg8ylation is a key step during autophagy where Atg8-family proteins are conjugated to the expanding phagophore. In addition to double-layered autophagic compartments, Atg8ylation occurs on various other cellular membranes and is emerging as a general eukaryotic membrane-tagging system comparable to that of ubiquitin tagging of proteins. While canonical autophagy has been characterized across eukaryotes, Atg8ylation beyond canonical autophagy has mostly been explored in mammals. ATG7 is an E1-like enzyme which participates in the three-step ubiquitin-like cascade that mediates Atg8-family protein conjugation. Apart from its role in Atg8ylation, several independent functions have been reported in mammals. Exploring functions of ATG7 from an evolutionary perspective highlights that Atg8ylation on single-layer membranes is conserved across eukaryotes. Although Atg8ylation-independent functions of ATG7 remain largely unexplored outside mammals, evidence from other eukaryotic clades suggests that some of these functional roles may be conserved. In this review, ATG7 functions are organized by eukaryotic clades to gain better understanding of their evolutionary history.Abbreviations: AD: active domain; CASM: conjugation of Atg8 to single layer membranes; EMT: endothelial-to-mesenchymal transition; ESCRT: endosomal sorting complexes required for transport; HFD: high-fat diet; LAP: LC3-associated phagocytosis; LECA: last eukaryotic common ancestor; NTD: N-terminal domain; PE: phosphatidylethanolamine; PS: phosphatidylserine; UBL: ubiquitin-like.