title: Pacer Mediates the Function of Class III PI3K and HOPS Complexes in Autophagosome Maturation by Engaging Stx17.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xiawei
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xiuling
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xianming
authors.initials: X
authors.lastname: Ding
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Jiang
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Shen
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: She
authors.initials: S
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou 310012, China. Electronic address: weihua.gong@gmail.com.
authors.forename: Weihua
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, Hangzhou 310058, China. Electronic address: qmsun@zju.edu.cn.
authors.forename: Qiming
authors.initials: Q
authors.lastname: Sun
mesh_terms: D000071182:Autophagosomes / Q000201:enzymology*; D001343:Autophagy; D000071183:Autophagy-Related Proteins / Q000235:genetics / Q000378:metabolism*; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011992:Endosomes / Q000201:enzymology; D004789:Enzyme Activation; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000201:enzymology; D054884:Host-Pathogen Interactions; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D066292:Lipid Droplets / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology; D008561:Membrane Fusion; D066329:Protein Aggregates; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D050765:Qa-SNARE Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012486:Salmonella typhimurium / Q000254:growth & development; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071183:Autophagy-Related Proteins; D047908:Intracellular Signaling Peptides and Proteins; D066329:Protein Aggregates; D050765:Qa-SNARE Proteins; C552537:RUBCN protein, human; C585115:RUBCNL protein, human; C551267:STX17 protein, human; D025521:Tumor Suppressor Proteins; C408122:UVRAG protein, human; D033921:Vesicular Transport Proteins; D058546:Class III Phosphatidylinositol 3-Kinases
keywords: Beclin1; HOPS; PI3KC3; Pacer; Rubicon; Stx-17; UVRAG; Vps34