title: The Vici Syndrome Protein EPG5 Is a Rab7 Effector that Determines the Fusion Specificity of Autophagosomes with Late Endosomes/Lysosomes.
abstract: Mutations in the human autophagy gene EPG5 cause the multisystem disorder Vici syndrome. Here we demonstrated that EPG5 is a Rab7 effector that determines the fusion specificity of autophagosomes with late endosomes/lysosomes. EPG5 is recruited to late endosomes/lysosomes by direct interaction with Rab7 and the late endosomal/lysosomal R-SNARE VAMP7/8. EPG5 also binds to LC3/LGG-1 (mammalian and C. elegans Atg8 homolog, respectively) and to assembled STX17-SNAP29 Qabc SNARE complexes on autophagosomes. EPG5 stabilizes and facilitates the assembly of STX17-SNAP29-VAMP7/8 trans-SNARE complexes, and promotes STX17-SNAP29-VAMP7-mediated fusion of reconstituted proteoliposomes. Loss of EPG5 activity causes abnormal fusion of autophagosomes with various endocytic vesicles, in part due to elevated assembly of STX17-SNAP25-VAMP8 complexes. SNAP25 knockdown partially suppresses the autophagy defect caused by EPG5 depletion. Our study reveals that EPG5 is a Rab7 effector involved in autophagosome maturation, providing insight into the molecular mechanism underlying Vici syndrome.
authors: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, PRC.
authors: Zheng
authors: Z
authors: Wang
authors: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, PRC; Department of Immunology, Peking University School of Basic Medical Science, Beijing 100191, PRC.
authors: Guangyan
authors: G
authors: Miao
authors: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, PRC.
authors: Xue
authors: X
authors: Xue
authors: College of Life Sciences, Nankai University, Tianjin 300071, PRC.
authors: Xiangyang
authors: X
authors: Guo
authors: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, PRC.
authors: Chongzhen
authors: C
authors: Yuan
authors: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, PRC.
authors: Zhaoyu
authors: Z
authors: Wang
authors: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, PRC.
authors: Gangming
authors: G
authors: Zhang
authors: Department of Immunology, Peking University School of Basic Medical Science, Beijing 100191, PRC.
authors: Yingyu
authors: Y
authors: Chen
authors: Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, PRC.
authors: Du
authors: D
authors: Feng
authors: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, PRC.
authors: Junjie
authors: J
authors: Hu
authors: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, PRC; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, PRC. Electronic address: hongzhang@sun5.ibp.ac.cn.
authors: Hong
authors: H
authors: Zhang
mesh_terms: D061085:Agenesis of Corpus Callosum / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D000071182:Autophagosomes / Q000378:metabolism* / Q000648:ultrastructure; D001343:Autophagy / Q000235:genetics; D000071183:Autophagy-Related Proteins; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002386:Cataract / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011992:Endosomes / Q000378:metabolism* / Q000648:ultrastructure; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D051907:Lysosomal Membrane Proteins; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D008561:Membrane Fusion; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D050765:Qa-SNARE Proteins / Q000235:genetics / Q000378:metabolism; D050766:Qb-SNARE Proteins / Q000235:genetics / Q000378:metabolism; D050767:Qc-SNARE Proteins / Q000235:genetics / Q000378:metabolism; D050683:R-SNARE Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D000071183:Autophagy-Related Proteins; D029742:Caenorhabditis elegans Proteins; C000592185:EPG5 protein, human; C587195:LGG-1 protein, C elegans; D051907:Lysosomal Membrane Proteins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D011506:Proteins; D050765:Qa-SNARE Proteins; D050766:Qb-SNARE Proteins; D050767:Qc-SNARE Proteins; D050683:R-SNARE Proteins; C494208:SNAP25 protein, human; C432420:SNAP29 protein, human; C551267:STX17 protein, human; D050825:Synaptosomal-Associated Protein 25; C121241:VAMP7 protein, human; C112938:VAMP8 protein, human; D033921:Vesicular Transport Proteins; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D020691:rab GTP-Binding Proteins
keywords: LC3; RAB effector; SNARE; autophagosome maturation; epg-5