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J. Biol. Chem., Vol. 282, Issue 47, 33908-33914, November 23, 2007

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Identification of SVIP as an Endogenous Inhibitor of Endoplasmic Reticulum-associated Degradation^*

Petek Ballar¹, Yongwang Zhong, Masami Nagahama^¶, Mitsuo Tagaya^||, Yuxian Shen, and Shengyun Fang²

From the University of Maryland Biotechnology Institute, Baltimore, Maryland 21201, ^¶University of Tokushima, Tokushima 770-8506, Japan, ^||Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo 192-0392, Japan, and Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201

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 CD3 from association with gp78 and p97/VCP, which is accompanied by decreases in CD3 ubiquitination and degradation. Silencing SVIP expression markedly enhances the formation of gp78-p97/VCP-Derlin1 complex, which correlates with increased degradation of CD3 and misfolded Z variant of -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.

Received for publication, May 30, 2007 , and in revised form, August 9, 2007.

^* This work was supported in part by National Institutes of Health Grant R01 GM69967 (to S. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ Supported in part by a fellowship from the Council of Higher Education of Republic of Turkey to the University of Ege.

² To whom correspondence should be addressed: Medical Biotechnology Center, University of Maryland Biotechnology Inst., UMBI Bldg., N359, 725 W. Lombard St., Baltimore, MD 21201. E-mail: fangs{at}umbi.umd.edu.

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