An endoplasmic reticulum (ER) membrane complex composed of SPFH1 and SPFH2 mediates the ER-associated degradation of inositol 1,4,5-trisphosphate receptors

J Biol Chem. 2009 Apr 17;284(16):10433-45. doi: 10.1074/jbc.M809801200. Epub 2009 Feb 24.

Abstract

How endoplasmic reticulum (ER) proteins that are substrates for the ER-associated degradation (ERAD) pathway are recognized for polyubiquitination and proteasomal degradation is largely unresolved. Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) form tetrameric calcium channels in ER membranes, whose primary role is to control the release of ER calcium stores, but whose levels are also regulated, in an activation-dependent manner, by the ERAD pathway. Here we report that the ER membrane protein SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex that binds to IP(3)R tetramers immediately after their activation and is required for their processing. The complex is ring-shaped (diameter approximately 250A(),) and RNA interference-mediated depletion of SPFH1 and SPFH2 blocks IP(3)R polyubiquitination and degradation. We propose that this novel SPFH1/2 complex is a recognition factor that targets IP(3)Rs and perhaps other substrates for ERAD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / ultrastructure
  • Gonadotropin-Releasing Hormone / metabolism
  • Humans
  • Inositol 1,4,5-Trisphosphate / metabolism
  • Inositol 1,4,5-Trisphosphate Receptors / genetics
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Membrane Microdomains / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Multiprotein Complexes / metabolism
  • Multiprotein Complexes / ultrastructure
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism*
  • RNA Interference
  • Rats
  • Ubiquitination

Substances

  • ERLIN1 protein, human
  • ERLIN2 protein, human
  • Inositol 1,4,5-Trisphosphate Receptors
  • Membrane Proteins
  • Multiprotein Complexes
  • Protein Isoforms
  • Gonadotropin-Releasing Hormone
  • Inositol 1,4,5-Trisphosphate
  • Proteasome Endopeptidase Complex