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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / metabolism*
  • Carrier Proteins / metabolism*
  • Endosomes / metabolism*
  • Membrane Fusion
  • Mutation
  • Nerve Tissue Proteins / metabolism
  • Phosphatidylinositol Phosphates / metabolism*
  • Vesicular Transport Proteins / metabolism
  • rab GTP-Binding Proteins / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • Carrier Proteins
  • Nerve Tissue Proteins
  • Phosphatidylinositol Phosphates
  • SORF-1 protein, C elegans
  • SORF-2 protein, C elegans
  • Vesicular Transport Proteins
  • WDR81 protein, human
  • WDR91 protein, human
  • bec-1 protein, C elegans
  • phosphatidylinositol 3-phosphate
  • rab GTP-Binding Proteins