Negative regulation of phosphatidylinositol 3-phosphate levels in early-to-late endosome conversion

  • J Cell Biol. 2016 Jan 18;212(2):181-98. doi: 10.1083/jcb.201506081.
Kai Liu  1 ,  Youli Jian  2 ,  Xiaojuan Sun  2 ,  Chengkui Yang  3 ,  Zhiyang Gao  2 ,  Zhili Zhang  3 ,  Xuezhao Liu  1 ,  Yang Li  2 ,  Jing Xu  2 ,  Yudong Jing  2 ,  Shohei Mitani  4 ,  Sudan He  3 ,  Chonglin Yang  5
Affiliations
  • 1. 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.
  • 2. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences. Beijing 100101, China.
  • 3. Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China.
  • 4. Department of Physiology, School of Medicine and Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Shinjuku-ku, Tokyo 162-0054, Japan.
  • 5. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences. Beijing 100101, China [email protected].
PMID: 26783301 DOI: 10.1083/jcb.201506081
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.