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Acetylation of Atg3 regulates the lipidation of the protein Atg8 in autophagy. The molecular mechanism behind this important biochemical event remains to be elucidated. We describe the first semi-synthesis of homogeneous K19/K48-diacetylated Atg3 through sequential hydrazide-based native chemical ligation. In vitro reconstitution experiments with the semi-synthetic proteins confirm that Atg3 acetylation can promote the lipidation of Atg8. We find that acetylation of Atg3 enhances its binding to phosphatidylethanolamine-containing liposomes and to endoplasmic reticulum, through which it promotes the lipidation process., Acetylation of Atg3 regulates lipidation of Atg8 and therefore autophagy, but the molecular mechanisms remain unclear. Here, Li et al. semi-synthesize diacetylated Atg3, allowing them to show that acetylated Atg3 enhances Atg8 lipidation by promoting interaction of Atg3 with liposomes containing physiological levels of phosphatidylethanolamine.