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.