title: Negative regulation of phosphatidylinositol 3-phosphate levels in early-to-late endosome conversion.
abstract: Phosphatidylinositol 3-phosphate (PtdIns3P) plays a central role in endosome fusion, recycling, sorting, and early-to-late endosome conversion, but the mechanisms that determine how the correct endosomal PtdIns3P level is achieved remain largely elusive. Here we identify two new factors, SORF-1 and SORF-2, as essential PtdIns3P regulators in Caenorhabditis elegans. Loss of sorf-1 or sorf-2 leads to greatly elevated endosomal PtdIns3P, which drives excessive fusion of early endosomes. sorf-1 and sorf-2 function coordinately with Rab switching genes to inhibit synthesis of PtdIns3P, allowing its turnover for endosome conversion. SORF-1 and SORF-2 act in a complex with BEC-1/Beclin1, and their loss causes elevated activity of the phosphatidylinositol 3-kinase (PI3K) complex. In mammalian cells, inactivation of WDR91 and WDR81, the homologs of SORF-1 and SORF-2, induces Beclin1-dependent enlargement of PtdIns3P-enriched endosomes and defective degradation of epidermal growth factor receptor. WDR91 and WDR81 interact with Beclin1 and inhibit PI3K complex activity. These findings reveal a conserved mechanism that controls appropriate PtdIns3P levels in early-to-late endosome conversion.
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences. Beijing 100101, China Graduate University of Chinese Academy of Sciences, Beijing 100109, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences. Beijing 100101, China.
authors.forename: Youli
authors.initials: Y
authors.lastname: Jian
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences. Beijing 100101, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Sun
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China.
authors.forename: Chengkui
authors.initials: C
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences. Beijing 100101, China.
authors.forename: Zhiyang
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences. Beijing 100101, China Graduate University of Chinese Academy of Sciences, Beijing 100109, China.
authors.forename: Xuezhao
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences. Beijing 100101, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences. Beijing 100101, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences. Beijing 100101, China.
authors.forename: Yudong
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Department of Physiology, School of Medicine and Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Shinjuku-ku, Tokyo 162-0054, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Mitani
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China.
authors.forename: Sudan
authors.initials: S
authors.lastname: He
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences. Beijing 100101, China clyang@genetics.ac.cn.
authors.forename: Chonglin
authors.initials: C
authors.lastname: Yang
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D008561:Membrane Fusion; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D018129:Phosphatidylinositol Phosphates; C000609631:SORF-1 protein, C elegans; C000609632:SORF-2 protein, C elegans; D033921:Vesicular Transport Proteins; C000609634:WDR81 protein, human; C000609633:WDR91 protein, human; C477268:bec-1 protein, C elegans; C055525:phosphatidylinositol 3-phosphate; D020691:rab GTP-Binding Proteins