Hrs and SNX3 Functions in Sorting and Membrane Invagination Within Multivesicular Bodies

PLoS Biol. 2008 Sep 2;6(9):e214. doi: 10.1371/journal.pbio.0060214.

Abstract

After internalization, ubiquitinated signaling receptors are delivered to early endosomes. There, they are sorted and incorporated into the intralumenal invaginations of nascent multivesicular bodies, which function as transport intermediates to late endosomes. Receptor sorting is achieved by Hrs--an adaptor--like protein that binds membrane PtdIns3P via a FYVE motif-and then by ESCRT complexes, which presumably also mediate the invagination process. Eventually, intralumenal vesicles are delivered to lysosomes, leading to the notion that EGF receptor sorting into multivesicular bodies mediates lysosomal targeting. Here, we report that Hrs is essential for lysosomal targeting but dispensable for multivesicular body biogenesis and transport to late endosomes. By contrast, we find that the PtdIns3P-binding protein SNX3 is required for multivesicular body formation, but not for EGF receptor degradation. PtdIns3P thus controls the complementary functions of Hrs and SNX3 in sorting and multivesicular body biogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / metabolism*
  • Endocytosis / physiology*
  • Endosomal Sorting Complexes Required for Transport
  • Endosomes / metabolism*
  • Epidermal Growth Factor / metabolism
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • HeLa Cells
  • Humans
  • Lysosome-Associated Membrane Glycoproteins / genetics
  • Lysosome-Associated Membrane Glycoproteins / metabolism
  • Lysosomes / metabolism*
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein Transport / physiology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sorting Nexins
  • Ubiquitin / metabolism
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*
  • rab5 GTP-Binding Proteins / genetics
  • rab5 GTP-Binding Proteins / metabolism

Substances

  • Endosomal Sorting Complexes Required for Transport
  • LAMP1 protein, human
  • Lysosome-Associated Membrane Glycoproteins
  • Phosphatidylinositol Phosphates
  • Phosphoproteins
  • Recombinant Fusion Proteins
  • SNX3 protein, human
  • Sorting Nexins
  • Ubiquitin
  • Vesicular Transport Proteins
  • early endosome antigen 1
  • hepatocyte growth factor-regulated tyrosine kinase substrate
  • phosphatidylinositol 3-phosphate
  • Epidermal Growth Factor
  • ErbB Receptors
  • rab5 GTP-Binding Proteins