An Endoplasmic Reticulum (ER) Membrane Complex Composed of SPFH1 and SPFH2 Mediates the ER-associated Degradation of Inositol 1,4,5-Trisphosphate Receptors
Open accessAbstract
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.
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The erlin1/2 complex binds to IP3 receptors immediately after their activation.
“whichhasbeenshownpreviouslytobindtoIP3 receptors immediately after their activation.”
From RNF170 Protein, an Endoplasmic Reticulum Membrane Ubiquitin Ligase, Mediates Inositol 1,4,5-Trisphosphate Receptor Ubiquitination and Degradation (2011) · cites this paper as [15]
The ER membrane-located erlin1/2 (SPFH1/2) complex associates rapidly with activated IP3 receptors and appears to be the element that selects them for ERAD.
“Additionally, we have recently found that the ER membrane-located erlin1/2 (SPFH1/2) complex associates rapidly with activated IP 3 receptors and appears to be the element that selects them for ERAD (14, 15).”
From RNF170 Protein, an Endoplasmic Reticulum Membrane Ubiquitin Ligase, Mediates Inositol 1,4,5-Trisphosphate Receptor Ubiquitination and Degradation (2011) · cites this paper as [15]
Erlin2 binding provides a measure of erlin1/2 complex binding.
“The binding of erlin2 (which provides a measure of erlin1/2 complex binding (15))”
From RNF170 Protein, an Endoplasmic Reticulum Membrane Ubiquitin Ligase, Mediates Inositol 1,4,5-Trisphosphate Receptor Ubiquitination and Degradation (2011) · cites this paper as [15]
By extrapolation, depletion of RNF170 did not inhibit the association of the erlin1/2 complex with activated IP3 receptors.
“extrapolation, the erlin1/2 complex (15) with activated IP 3 receptors (Fig. 5 C , lane 3 )”
From RNF170 Protein, an Endoplasmic Reticulum Membrane Ubiquitin Ligase, Mediates Inositol 1,4,5-Trisphosphate Receptor Ubiquitination and Degradation (2011) · cites this paper as [15]
p97 associates with IP3 receptors after they have been polyubiquitinated.
“which associates with IP 3 receptors after they have been polyubiquitinated (4, 14, 15).”
From RNF170 Protein, an Endoplasmic Reticulum Membrane Ubiquitin Ligase, Mediates Inositol 1,4,5-Trisphosphate Receptor Ubiquitination and Degradation (2011) · cites this paper as [15]
α-transaldolase is a cytosolic marker.
“the cytosolic marker 𝛂 -transaldolase (14, 15)”
From RNF170 Protein, an Endoplasmic Reticulum Membrane Ubiquitin Ligase, Mediates Inositol 1,4,5-Trisphosphate Receptor Ubiquitination and Degradation (2011) · cites this paper as [15]
The erlin1/2 complex is located in the ER membrane.
“Because IP 3 receptors (1) and the erlin1/2 complex (15) are located in the ER membrane”
From RNF170 Protein, an Endoplasmic Reticulum Membrane Ubiquitin Ligase, Mediates Inositol 1,4,5-Trisphosphate Receptor Ubiquitination and Degradation (2011) · cites this paper as [15]
The erlin1/2 complex acts as a recognition factor that selects activated IP3 receptors for degradation via the ERAD pathway.
“It is thought that the intralumenal regions of the erlin1/2 complex interact with intralumenal regions of activated IP 3 receptors and that the erlin1/2 complex acts as a 'recognition factor' that selects activated IP 3 receptors for degradation via the ERAD pathway (2, 15).”
From RNF170 Protein, an Endoplasmic Reticulum Membrane Ubiquitin Ligase, Mediates Inositol 1,4,5-Trisphosphate Receptor Ubiquitination and Degradation (2011) · cites this paper as [15]
The intralumenal regions of the erlin1/2 complex interact with intralumenal regions of activated IP3 receptors.
“It is thought that the intralumenal regions of the erlin1/2 complex interact with intralumenal regions of activated IP 3 receptors and that the erlin1/2 complex acts as a 'recognition factor' that selects activated IP 3 receptors for degradation via the ERAD pathway (2, 15).”
From RNF170 Protein, an Endoplasmic Reticulum Membrane Ubiquitin Ligase, Mediates Inositol 1,4,5-Trisphosphate Receptor Ubiquitination and Degradation (2011) · cites this paper as [15]
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Cites
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BOK Is a Non-canonical BCL-2 Family Effector of Apoptosis Regulated by ER-Associated Degradation
Llambi, F., Wang, Y.-M., Victor, B., Yang, M., Schneider, D. M., Gingras, S., Parsons, M. J., Zheng, J. H., Brown, S. A., Pelletier, S., et al. (2016) · Cell · doi:10.1016/j.cell.2016.02.026 · Cited by 261 · see citing works
Lu, J. P., Wang, Y., Sliter, D. A., Pearce, M. M. P., & Wojcikiewicz, R. J. H. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.251983 · Cited by 102 · see citing works
Self-citation
- Authors
- Pearce, M. M. P., Wormer, D. B., Wilkens, S., & Wojcikiewicz, R. J. H.
- Affiliations
- SUNY Upstate Medical University (US)
- Corresponding author
- Wojcikiewicz, Richard J.H.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-04
- Volume
- 284
- Issue
- 16
- Pages
- 10433-10445
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2667730
- OpenAlex
- W2068688570
- Cited by
- 114
- References
- 1
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 12 · 2023: 6 · 2022: 8 · 2021: 7 · 2020: 9 · 2019: 4 · 2018: 3 · 2017: 6 · 2016: 7 · 2015: 3 · 2014: 4 · 2013: 2 · 2012: 15
- FWCI
- 3.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pharmaceutical Research and Manufacturers of America Foundation
- National Institutes of Health (DK49194)
- National Cancer Institute (CA100246, R01CA100246)
- National Institute of General Medical Sciences (GM 58600, R01GM058600)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 49194)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- IP3 receptor, ER-associated degradation, polyubiquitination, proteasomal degradation, calcium channel regulation, ER calcium stores
- MeSH terms
- Animals, Cell Line, Endoplasmic Reticulum, Humans, Gonadotropin-Releasing Hormone, Membrane Proteins, Nerve Tissue Proteins, Inositol 1,4,5-Trisphosphate, Protein Isoforms, Membrane Microdomains, RNA Interference, Multiprotein Complexes, Proteasome Endopeptidase Complex, Rats, Inositol 1,4,5-Trisphosphate Receptors, Ubiquitination
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