2. Academic Validation
  3. Pacer Is a Mediator of mTORC1 and GSK3-TIP60 Signaling in Regulation of Autophagosome Maturation and Lipid Metabolism

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.
Xiawei Cheng 1,  Xiuling Ma 1,  Qi Zhu 1,  Dandan Song 1,  Xianming Ding 1,  Lin Li 2,  Xiao Jiang 1,  Xinyi Wang 1,  Rui Tian 1,  Hua Su 1,  Zhirong Shen 2,  She Chen 2,  Ting Liu 3,  Weihua Gong 4,  Wei Liu 1,  Qiming Sun 5
Affiliations

Affiliations

  • 1 Department of Biochemistry, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 2 National Institute of Biological Sciences, Beijing 102206, China.
  • 3 Department of Cell Biology, and Department of General Surgery of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 4 Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310012, China.
  • 5 Department of Biochemistry, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: qmsun@zju.edu.cn.
PMID: 30704899 DOI: 10.1016/j.molcel.2018.12.017
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.

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