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J Cell Biol. 2016 Jan 18;212(2):181-98. doi: 10.1083/jcb.201506081.

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

Author information

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 clyang@genetics.ac.cn.

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.

PMID:
26783301
PMCID:
PMC4738380
DOI:
10.1083/jcb.201506081
[Indexed for MEDLINE]
Free PMC Article

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