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

被引:107
作者
Cheng, Xiawei [1 ]
Ma, Xiuling [1 ]
Ding, Xianming [1 ]
Li, Lin [2 ]
Jiang, Xiao [1 ]
Shen, Zhirong [2 ]
Chen, She [2 ]
Liu, Wei [1 ,3 ]
Gong, Weihua [4 ]
Sun, Qiming [1 ]
机构
[1] Zhejiang Univ, Sch Med, Dept Biochem & Mol Biol, Hangzhou 310058, Zhejiang, Peoples R China
[2] Natl Inst Biol Sci, Beijing 102206, Peoples R China
[3] Zhejiang Univ, Affiliated Hosp 1, Collaborat Innovat Ctr Diag & Treatment Infect Di, Sch Med, Hangzhou 310003, Zhejiang, Peoples R China
[4] Zhejiang Univ, Dept Surg, Affiliated Hosp 2, Sch Med, Hangzhou 310012, Zhejiang, Peoples R China
基金
美国国家科学基金会;
关键词
PHOSPHATIDYLINOSITOL 3-KINASE COMPLEX; SNARE SYNTAXIN 17; C-VPS COMPLEX; LYSOSOME FUSION; ENDOSOME MATURATION; RAB7; EFFECTOR; UVRAG; RUBICON; PROTEIN; ATG14L;
D O I
10.1016/j.molcel.2017.02.010
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
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 autophagosometo 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 auto-phagosomal 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.
引用
收藏
页码:1029 / +
页数:20
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