Pacer Is a Mediator of mTORC1 and GSK3-TIP60 Signaling in Regulation of Autophagosome Maturation and Lipid Metabolism

mTORC1 and GSK3 play critical roles in early stages of (macro)autophagy, but how they regulate late steps of autophagy remains poorly understood. Here we show that mTORC1 and GSK3-TIP60 signaling converge to modulate autophagosome maturation through Pacer, an autophagy regulator that was identified in our recent study. Hepatocyte-specific Pacer knockout in mice results in impaired autophagy flux, glycogen and lipid accumulation, and liver fibrosis. Under nutrient-rich conditions, mTORC1 phosphorylates Pacer at serine157 to disrupt the association of Pacer with Stx17 and the HOPS complex and thus abolishes Pacer-mediated autophagosome maturation. Importantly, dephosphorylation of Pacer under nutrient-deprived conditions promotes TIP60-mediated Pacer acetylation, which facilitates HOPS complex recruitment and is required for autophagosome maturation and lipid droplet clearance. This work not only identifies Pacer as a regulator in hepatic autophagy and liver homeostasis in vivo but also reveals a signal integration mechanism involved in late stages of autophagy and lipid metabolism. [Display omitted] •Pacer is a regulator of hepatic autophagy and liver homeostasis•Pacer is directly phosphorylated by mTORC1 under nutrient-rich conditions•Dephosphorylated Pacer is acetylated by the GSK3-TIP60 pathway•Pacer acetylation promotes autophagosome maturation and lipid metabolism Cheng et al. demonstrate that Pacer is essential for hepatic autophagy and liver homeostasis. Under autophagy induction conditions, mTORC1-mediated Pacer phosphorylation is repressed, which enables Pacer acetylation by the GSK3-TIP60 pathway. Pacer acetylation appears to be crucial for autolysosome formation and autophagic lipolysis.