CoChat
Sign Up
Cited by 33Ubiquitin and proteasome pathwaysEndoplasmic Reticulum Stress and DiseaseIon Channels and Receptors

SPFH1 and SPFH2 mediate the ubiquitination and degradation of inositol 1,4,5-trisphosphate receptors in muscarinic receptor-expressing HeLa cells

Open access
Wang, Yuan, Pearce, Margaret M.P., Sliter, Danielle A., Olzmann, James A., Christianson, John C., Kopito, Ron R., Boeckmann, Stephanie, Gagen, Christine +3 more·2009·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
DOI 10.1016/j.bbamcr.2009.09.004PMC PMC2764810
Open this paper in CoChat — free accountOpen PDF

Abstract

Inositol 1,4,5-trisphosphate (IP(3)) receptors are endoplasmic reticulum (ER) membrane calcium channels that, upon activation, become substrates for the ER-associated degradation (ERAD) pathway. While it is clear that IP(3) receptors are polyubiquitinated and are transferred to the proteasome by a p97-based complex, currently very little is known about the proteins that initially select activated IP(3) receptors for ERAD. Here, we have transfected HeLa cells to stably express m3 muscarinic receptors to allow for the study of IP(3) receptor ERAD in this cell type, and show that IP(3) receptors are polyubiquitinated and then degraded by the proteasome in response to carbachol, a muscarinic agonist. In seeking to identify proteins that mediate IP(3) receptor ERAD we found that both SPFH1 and SPFH2 (also known as erlin 1 and erlin 2), which exist as a hetero-oligomeric complex, rapidly associate with IP(3) receptors in a manner that precedes polyubiquitination and the association of p97. Suppression of SPFH1 and SPFH2 expression by RNA interference markedly inhibited carbachol-induced IP(3) receptor polyubiquitination and degradation, but did not affect carbachol-induced calcium mobilization or IkappaBalpha processing, indicating that the SPFH1/2 complex is a key player in IP(3) receptor ERAD, acting at a step after IP(3) receptor activation, but prior to IP(3) receptor polyubiquitination. Suppression of SPFH1 and SPFH2 expression had only slight effects on the turnover of some exogenous model ERAD substrates, and had no effect on sterol-induced ERAD of endogenous 3-hydroxy-3-methylglutaryl-CoA reductase. Overall, these studies show that m3 receptor-expressing HeLa cells are a valuable system for studying IP(3) receptor ERAD, and suggest that the SPFH1/2 complex is a factor that selectively mediates the ERAD of activated IP(3) receptors.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.bbamcr.2009.09.004

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 33

  1. [1]Vembar SS Brodsky JL 2008 One step at a time: Endoplasmic reticulum-associated degradation Nat Rev Mol Cell Biol 9 944 957 19002207 PMC2654601
  2. [2]Wojcikiewicz RJH Pearce MMP Sliter DA Wang Y 2009 When worlds collide: IP3 receptors and the ERAD pathway Cell Calcium 46 147 153 19709743 PMC2752845
  3. [3]Hampton RY Garza RM 2009 Protein quality control as a strategy for cellular regulation: lessons from ubiquitin-mediated regulation of the sterol pathway Chem Rev in press PMC8530524 19243134
  4. [4]Foskett JK White C Cheung KH Mak DD 2007 Inositol trisphosphate receptor Ca2+ release channels Physiol Rev 87 593 658 17429043 PMC2901638
  5. [5]Bokkala S Joseph SK 1997 Angiotensin II-induced down-regulation of inositol trisphosphate receptors in WB rat liver epithelial cells. Evidence for involvement of the proteasome pathway J Biol Chem 272 12454 12461 9139693
  6. [6]Oberdorf J Webster JM Zhu CC Luo SG Wojcikiewicz RJ 1999 Down-regulation of types I, II and III inositol 1,4,5-trisphosphate receptors is mediated by the ubiquitin/proteasome pathway Biochem J 339 453 461 10191279 PMC1220177
  7. [7]Wojcikiewicz RJH Xu Q Webster JM Alzayady K Gao C 2003 Ubiquitination and proteasomal degradation of endogenous and exogenous inositol 1,4,5-trisphosphate receptors in alpha T3-1 anterior pituitary cells J Biol Chem 278 940 947 12421829
  8. [9]Webster JM Tiwari S Weissman AM Wojcikiewicz RJH 2003 Inositol 1,4,5-trisphosphate receptor ubiquitination is mediated by mammalian Ubc7, a component of the endoplasmic reticulum-associated degradation pathway, and is inhibited by chelation of intracellular Zn2+ J Biol Chem 278 38238 38246 12869571
  9. [10]Alzayady KJ Wojcikiewicz RJH 2005 The role of Ca2+ in triggering inositol 1,4,5-trisphosphate receptor ubiquitination Biochem J 392 601 606 16134970 PMC1316300
  10. [11]Hattori M Suzuki AZ Higo T Miyauchi H Michikawa T Nakamura T Inoue T Mikoshiba K 2004 Distinct Roles of Inositol 1,4,5-Trisphosphate Receptor Types 1 and 3 in Ca2+ Signaling J Biol Chem 279 11967 11975 14707143
  11. [12]Wojcik C Fabunmi R DeMartino GN 2005 Modulation of gene expression by RNAi Methods in Molecular Medicine 108 381 393 16028696
  12. [13]Browman DT Resek ME Zajchowski LD Robbins SM 2006 Erlin-1 and erlin-2 are novel members of the prohibitin family of proteins that define lipid-raft-like domains of the ER J Cell Sci 119 3149 3160 16835267
  13. [14]Browman DT Hoegg MB Robbins SM 2007 The SPFH domain-containing proteins: More than lipid raft markers Trends Cell Biol 17 394 402 17766116
  14. [15]Pearce MMP Wang Y Kelley GG Wojcikiewicz RJH 2007 SPFH2 mediates the endoplasmic reticulum-associated degradation of inositol 1,4,5-trisphosphate receptors and other substrates in mammalian cells J Biol Chem 282 20104 20115 17502376
  15. [16]Roitelman J Olender EH Bar-Nun S Dunn WA Jr Simoni RD 1992 Immunological evidence for eight spans in the membrane domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase: implications for enzyme degradation in the endoplasmic reticulum J Cell Biol 117 959 973 1374417 PMC2289486
  16. [17]Goldstein JL Basu SK Brown MS 1983 Receptor-mediated endocytosis of low-density lipoprotein in cultured cells Methods Enzymol 98 241 260 6321901
  17. [18]Bence NF Sampat RM Kopito RR 2001 Impairment of the ubiquitin-proteasome system by protein aggregation Science 292 1552 1555 11375494
  18. [19]Yu H Kopito RR 1999 The role of multiubiquitination in dislocation and degradation of the alpha subunit of the T cell antigen receptor J Biol Chem 274 36852 36858 10601236
  19. [20]Sifers RN Brashears-Macatee S Kidd VJ Muensch H Woo SL 1988 A frameshift mutation results in a truncated alpha1-antitrypsin that is retained within the rough endoplasmic reticulum J Biol Chem 263 7330 7335 3259232
  20. [21]Sekijima Y Wiseman RL Matteson J Hammarström P Miller SR Sawkar AR Balch WE Kelly JW 2005 The biological and chemical basis for tissue-selective amyloid disease Cell 121 73 85 15820680
  21. [22]DeLaBarre B Christianson JC Kopito RR Brunger AT 2006 Central pore residues mediate the p97/VCP activity required for ERAD Mol Cell 22 451 462 16713576
  22. [23]Pearce MMP Wormer DB Wilkens S Wojcikiewicz RJH 2009 An ER membrane complex composed of SPFH1 and SPFH2 mediates the ER-associated degradation of IP3 receptors J Biol Chem 284 10433 10445 19240031 PMC2667730
  23. [24]Roitelman J Simoni RD 1992 Distinct sterol and nonsterol signals for the regulated degradation of 3-hydroxy-3-methylglutaryl-CoA reductase J Biol Chem 267 25264 25273 1460026
  24. [25]Ravid T Doolman R Avner R Harats D Roitelman J 2000 The ubiquitin-proteasome pathway mediates the regulated degradation of mammalian 3-Hydroxy-3-methylglutaryl-coenzyme A reductase J Biol Chem 275 35840 35847 10964918
  25. [26]Matsu-ura T Michikawa T Inoue T Miyawaki A Yoshida M Mikoshiba K 2006 Cytosolic inositol 1,4,5-trisphosphate dynamics during intracellular calcium oscillations in living cells J Cell Biol 173 755 765 16754959 PMC2063891
  26. [27]Ye Y Meyer HH Rapoport TA 2003 Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: Dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains J Cell Biol 162 71 84 12847084 PMC2172719
  27. [28]Hoegg MB Browman DT Resek ME Robbins SM 2009 Distinct regions within the erlins are required for oligomerization and association with high molecular weight complexes J Biol Chem 284 7766 7776 19131330 PMC2658070
  28. [29]Alkalay I Yaron A Hatzubai A Orian A Ciechanover A Ben-Neriah Y 1995 Stimulus-dependent IκBα phosphorylation marks the NF-κB inhibitor for degradation via the ubiquitin-proteasome pathway Proc Natl Acad Sci USA 92 10599 10603 7479848 PMC40659
  29. [30]Xu Q Farah M Webster JM Wojcikiewicz RJH 2004 Bortezomib rapidly suppresses ubiquitin thiolesterification to ubiquitin-conjugating enzymes and inhibits ubiquitination of histones and type I inositol 1,4,5-trisphosphate receptor Mol Cancer Ther 3 1263 1269 15486193
  30. [31]Wojcikiewicz RJ Furuichi T Nakade S Mikoshiba K Nahorski SR 1994 Muscarinic receptor activation down-regulates the type I inositol 1,4,5- trisphosphate receptor by accelerating its degradation J Biol Chem 269 7963 7969 8132516
  31. [32]Wang X Venable J LaPointe P Hutt DM Koulov AV Coppinger J Gurkan C Kellner W Matteson J Plutner H Riordan JR Kelly JW Yates JR Iii Balch WE 2006 Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis Cell 127 803 815 17110338
  32. [33]Lyssand JS DeFino MC Tang XB Hertz AL Feller DB Wacker JL Adams ME Hague C 2008 Blood pressure is regulated by an α1D-adrenergic receptor/dystrophin signalosome J Biol Chem 283 18792 18800 18468998 PMC2441552
  33. [34]Sliter DA Kubota K Kirkpatrick DS Alzayady KJ Gygi SP Wojcikiewicz RJH 2008 Mass spectrometric analysis of type 1 inositol 1,4,5-trisphosphate receptor ubiquitination J Biol Chem 283 35319 35328 18955483 PMC2602886

Cited by

Sorted by citations

Authors
Wang, Y., Pearce, M. M. P., Sliter, D. A., Olzmann, J. A., Christianson, J. C., Kopito, R. R., Boeckmann, S., Gagen, C., Leichner, G. S., Roitelman, J., & Wojcikiewicz, R. J. H.
Affiliations
  • SUNY Upstate Medical University (US)
  • Stanford University (US)
  • Sheba Medical Center (IL)
Corresponding author
Wojcikiewicz, Richard J.H.
ORCID
Venue
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Publisher
Elsevier BV
Published
2009-11
Volume
1793
Issue
11
Pages
1710-1718
ISSN
0167-4889 (ISSN-L)
DOI
10.1016/j.bbamcr.2009.09.004
PMC
PMC2764810
OpenAlex
W2168429837
Cited by
33
References
1
Citations by year
2026: 2 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 4 · 2014: 1 · 2013: 1 · 2012: 5
FWCI
1.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (DK049194, GM074874)
  • Pharmaceutical Research and Manufacturers of America Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
IP3 receptor, ER-associated degradation, polyubiquitination, proteasomal degradation, VCP, M3 muscarinic receptor, carbachol, endoplasmic reticulum calcium channels, protein turnover
MeSH terms
HeLa Cells, Humans, Hydroxymethylglutaryl CoA Reductases, Membrane Proteins, Nerve Tissue Proteins, Gene Expression, Receptor, Muscarinic M3, Inositol 1,4,5-Trisphosphate Receptors, Ubiquitination

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review