During macroautophagy/autophagy, ATG8-family proteins undergo 2 distinct proteolytic processing events. First, in support of phagophore growth, ATG8 is cleaved by ATG4 to expose a glycine at the COOH-terminus. The exposed glycine is then utilized in a series of ubiquitin-like reactions culminating in the covalent attachment of the ATG8-family protein to the phospholipid phosphatidylethanolamine (PE). Second, following autophagosome maturation, each ATG8 protein is recycled off the membrane by an ATG4-mediated cleavage that breaks the bond between glycine and PE. Thus, ATG4 is responsible for both early and late cleavage events on distinct pools (soluble and lipid-attached) of ATG8-related proteins. ATG8-family proteases are included within MEROPS family C54. (Adapted from PMID:29458288.)