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PMID: 19240031 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

The Journal of biological chemistry ·Vol. 284 ·No. 16 ·2009-04-17 ·Pages 10433-45

Pearce MM, Wormer DB, Wilkens S, Wojcikiewicz RJ

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.

MeSH Terms
Animals Cell Line Endoplasmic Reticulum/metabolism,ultrastructure Gonadotropin-Releasing Hormone/metabolism Humans Inositol 1,4,5-Trisphosphate/metabolism Inositol 1,4,5-Trisphosphate Receptors/genetics,metabolism Membrane Microdomains/chemistry Membrane Proteins/genetics,metabolism Multiprotein Complexes/metabolism,ultrastructure Nerve Tissue Proteins Proteasome Endopeptidase Complex/metabolism Protein Isoforms/genetics,metabolism RNA Interference Rats Ubiquitination
Chemicals
ERLIN1 protein, human ERLIN2 protein, human Inositol 1,4,5-Trisphosphate Receptors Membrane Proteins Multiprotein Complexes Nerve Tissue Proteins Protein Isoforms Gonadotropin-Releasing Hormone Inositol 1,4,5-Trisphosphate Proteasome Endopeptidase Complex
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Pearce Margaret M P
Departments of Pharmacology and Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York 13210, USA.
Wormer Duncan B
Wilkens Stephan
Wojcikiewicz Richard J H
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M809801200
Published
2009-04-17
Epub
2009-00-24
Pages
10433-45
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2667730
Subset
IM
Grants
NCI NIH HHS · CA100246 · United States
NIDDK NIH HHS · DK49194 · United States
NIGMS NIH HHS · GM58600 · United States
External Links
PubMed source DOI: 10.1074/jbc.M809801200 PMC Full Text View journal details
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