Cited by 93Endoplasmic Reticulum Stress and DiseaseHeat shock proteins researchUbiquitin and proteasome pathways

Identification of SVIP as an endogenous inhibitor of endoplasmic reticulum-associated degradation

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Ballar, Petek, Zhong, Yongwang, Nagahama, Masami, Tagaya, Mitsuo, Shen, Yuxian, Fang, Shengyun·2007·Journal of Biological Chemistry

Abstract

Misfolded proteins in the endoplasmic reticulum (ER) are eliminated by a process known as ER-associated degradation (ERAD), which starts with misfolded protein recognition, followed by ubiquitination, retrotranslocation to the cytosol, deglycosylation, and targeting to the proteasome for degradation. Actions of multisubunit protein machineries in the ER membrane integrate these steps. We hypothesized that regulation of the multisubunit machinery assembly is a mechanism by which ERAD activity is regulated. To test this hypothesis, we investigated the potential regulatory role of the small p97/VCP-interacting protein (SVIP) on the formation of the ERAD machinery that includes ubiquitin ligase gp78, AAA ATPase p97/VCP, and the putative channel Derlin1. We found that SVIP is anchored to microsomal membrane via myristoylation and co-fractionated with gp78, Derlin1, p97/VCP, and calnexin to the ER. Like gp78, SVIP also physically interacts with p97/VCP and Derlin1. Overexpression of SVIP blocks unassembled CD3delta from association with gp78 and p97/VCP, which is accompanied by decreases in CD3delta ubiquitination and degradation. Silencing SVIP expression markedly enhances the formation of gp78-p97/VCP-Derlin1 complex, which correlates with increased degradation of CD3delta and misfolded Z variant of alpha-1-antitrypsin, established substrates of gp78. These results suggest that SVIP is an endogenous inhibitor of ERAD that acts through regulating the assembly of the gp78-p97/VCP-Derlin1 complex.

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Crossref · 10.1074/jbc.m704446200

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Authors
Ballar, P., Zhong, Y., Nagahama, M., Tagaya, M., Shen, Y., & Fang, S.
Affiliations
  • University of Maryland, Baltimore (US)
  • Tokushima University (JP)
  • Tokyo University of Pharmacy and Life Sciences (JP)
Corresponding author
Fang, Shengyun
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2007-11
Volume
282
Issue
47
Pages
33908-33914
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2073337768
Cited by
93
References
37
Citations by year
2026: 4 · 2025: 2 · 2024: 7 · 2023: 12 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 5 · 2018: 1 · 2017: 9 · 2016: 3 · 2015: 6 · 2013: 6 · 2012: 7
FWCI
2.34
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Institute of General Medical Sciences (R01-GM69967, R01GM069967)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
ER-associated degradation, gp78, VCP/p97, protein misfolding, ubiquitination, retrotranslocation, proteasomal degradation, protein complex formation, myristoylation, calnexin, endoplasmic reticulum
MeSH terms
Valosin Containing Protein, Adenosine Triphosphatases, alpha 1-Antitrypsin, Carrier Proteins, Cell Line, Endoplasmic Reticulum, Humans, Membrane Proteins, Nuclear Proteins, Protein Processing, Post-Translational, CD3 Complex, Protein Folding, Receptors, Cytokine, Cell Cycle Proteins, Gene Silencing, Phosphate-Binding Proteins, Calnexin, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Ubiquitination, Receptors, Autocrine Motility Factor, Proteasome Inhibitors

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