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

Mol Cell. 2019 Feb 21;73(4):788-802.e7. doi: 10.1016/j.molcel.2018.12.017. Epub 2019 Jan 28.

Abstract

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.

Keywords: GSK3; TIP60; acetylation; autophagosome maturation; lipid metabolism; mTORC1; pacer; phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Autophagosomes / enzymology*
  • Autophagosomes / pathology
  • Autophagy*
  • Autophagy-Related Proteins / genetics
  • Autophagy-Related Proteins / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism*
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lipid Droplets / metabolism
  • Lipid Metabolism*
  • Liver / enzymology*
  • Liver / pathology
  • Lysine Acetyltransferase 5 / genetics
  • Lysine Acetyltransferase 5 / metabolism*
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Membrane Proteins
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / enzymology
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphate-Binding Proteins / genetics
  • Phosphate-Binding Proteins / metabolism*
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Qa-SNARE Proteins / genetics
  • Qa-SNARE Proteins / metabolism
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*

Substances

  • Autophagy-Related Proteins
  • Carrier Proteins
  • HOPS protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Nuclear Proteins
  • Phosphate-Binding Proteins
  • Qa-SNARE Proteins
  • RUBCNL protein, human
  • Rubcnl protein, mouse
  • Stx17 protein, mouse
  • Trans-Activators
  • KAT5 protein, human
  • Kat5 protein, mouse
  • Lysine Acetyltransferase 5
  • Mechanistic Target of Rapamycin Complex 1
  • Glycogen Synthase Kinase 3