The PH domain proteins IPIP27A and B link OCRL1 to receptor recycling in the endocytic pathway

Mol Biol Cell. 2011 Mar 1;22(5):606-23. doi: 10.1091/mbc.E10-08-0730. Epub 2011 Jan 13.

Abstract

Mutation of the inositol polyphosphate 5-phosphatase OCRL1 results in two disorders in humans, namely Lowe syndrome (characterized by ocular, nervous system, and renal defects) and type 2 Dent disease (in which only the renal symptoms are evident). The disease mechanisms of these syndromes are poorly understood. Here we identify two novel OCRL1-binding proteins, termed inositol polyphosphate phosphatase interacting protein of 27 kDa (IPIP27)A and B (also known as Ses1 and 2), that also bind the related 5-phosphatase Inpp5b. The IPIPs bind to the C-terminal region of these phosphatases via a conserved motif similar to that found in the signaling protein APPL1. IPIP27A and B, which form homo- and heterodimers, localize to early and recycling endosomes and the trans-Golgi network (TGN). The IPIPs are required for receptor recycling from endosomes, both to the TGN and to the plasma membrane. Our results identify IPIP27A and B as key players in endocytic trafficking and strongly suggest that defects in this process are responsible for the pathology of Lowe syndrome and Dent disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Cell Membrane / metabolism
  • Conserved Sequence / genetics
  • Endocytosis*
  • Endosomes / metabolism
  • HeLa Cells
  • Humans
  • Hydrolases / metabolism
  • Lysosomes / enzymology
  • Molecular Sequence Data
  • Mutation / genetics
  • Oculocerebrorenal Syndrome / enzymology
  • Oculocerebrorenal Syndrome / genetics
  • Phosphoric Monoester Hydrolases / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Transport
  • RNA, Small Interfering / metabolism
  • Receptors, Transferrin / metabolism*
  • Secretory Pathway*
  • Shiga Toxin / metabolism
  • Vesicular Transport Proteins / chemistry
  • Vesicular Transport Proteins / metabolism*
  • trans-Golgi Network / metabolism

Substances

  • PHETA1 protein, human
  • PHETA2 protein, human
  • RNA, Small Interfering
  • Receptors, Transferrin
  • Vesicular Transport Proteins
  • Shiga Toxin
  • Hydrolases
  • Phosphoric Monoester Hydrolases
  • OCRL protein, human