title: An endoplasmic reticulum (ER) membrane complex composed of SPFH1 and SPFH2 mediates the ER-associated degradation of inositol 1,4,5-trisphosphate receptors.
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.
authors.affiliation: Departments of Pharmacology and Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York 13210, USA.
authors.forename: Margaret M P
authors.initials: MM
authors.lastname: Pearce
authors.forename: Duncan B
authors.initials: DB
authors.lastname: Wormer
authors.forename: Stephan
authors.initials: S
authors.lastname: Wilkens
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Wojcikiewicz
mesh_terms: D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D021962:Membrane Microdomains / Q000737:chemistry; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism / Q000648:ultrastructure; D009419:Nerve Tissue Proteins; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D054875:Ubiquitination
chemical_list: C418605:ERLIN1 protein, human; C121703:ERLIN2 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D007987:Gonadotropin-Releasing Hormone; D015544:Inositol 1,4,5-Trisphosphate; D046988:Proteasome Endopeptidase Complex