2. Academic Validation
  3. Pacer Mediates the Function of Class III PI3K and HOPS Complexes in Autophagosome Maturation by Engaging Stx17

Pacer Mediates the Function of Class III PI3K and HOPS Complexes in Autophagosome Maturation by Engaging Stx17

  • Mol Cell. 2017 Mar 16;65(6):1029-1043.e5. doi: 10.1016/j.molcel.2017.02.010.
Xiawei Cheng 1,  Xiuling Ma 1,  Xianming Ding 1,  Lin Li 2,  Xiao Jiang 1,  Zhirong Shen 2,  She Chen 2,  Wei Liu 3,  Weihua Gong 4,  Qiming Sun 5
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
  • 2 National Institute of Biological Sciences, Beijing 102206, China.
  • 3 Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, Hangzhou 310058, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
  • 4 Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou 310012, China. Electronic address: [email protected].
  • 5 Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
PMID: 28306502 DOI: 10.1016/j.molcel.2017.02.010
Abstract

Class III PI3-kinase (PI3KC3) is essential for Autophagy initiation, but whether PI3KC3 participates in other steps of Autophagy remains unknown. The HOPS complex mediates the fusion of intracellular vesicles to lysosome, but how HOPS specifically tethers autophagosome to lysosome remains elusive. Here, we report Pacer (protein associated with UVRAG as Autophagy enhancer) as a regulator of Autophagy. Pacer localizes to autophagic structures and positively regulates autophagosome maturation. Mechanistically, Pacer antagonizes Rubicon to stimulate Vps34 kinase activity. Next, Pacer recruits PI3KC3 and HOPS complexes to the autophagosome for their site-specific activation by anchoring to the autophagosomal SNARE Stx17. Furthermore, Pacer is crucial for the degradation of hepatic lipid droplets, the suppression of Salmonella Infection, and the clearance of protein aggregates. These results not only identify Pacer as a crucial multifunctional enhancer in Autophagy but also uncover both the involvement of PI3KC3 and the mediators of HOPS's specific tethering activity in autophagosome maturation.

Keywords

Beclin1; HOPS; PI3KC3; Pacer; Rubicon; Stx-17; UVRAG; Vps34.

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