Identification of SVIP as an endogenous inhibitor of endoplasmic reticulum-associated degradation.
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.
Mesh Terms:
Adenosine Triphosphatases, Antigens, CD3, Calnexin, Cell Cycle Proteins, Cell Line, Endoplasmic Reticulum, Gene Silencing, Humans, Membrane Proteins, Nuclear Proteins, Proteasome Endopeptidase Complex, Protein Folding, Protein Processing, Post-Translational, Receptors, Cytokine, Ubiquitin-Protein Ligases, Ubiquitination, alpha 1-Antitrypsin
Adenosine Triphosphatases, Antigens, CD3, Calnexin, Cell Cycle Proteins, Cell Line, Endoplasmic Reticulum, Gene Silencing, Humans, Membrane Proteins, Nuclear Proteins, Proteasome Endopeptidase Complex, Protein Folding, Protein Processing, Post-Translational, Receptors, Cytokine, Ubiquitin-Protein Ligases, Ubiquitination, alpha 1-Antitrypsin
J. Biol. Chem.
Date: Nov. 23, 2007
PubMed ID: 17872946
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