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J. Biol. Chem., Vol. 281, Issue 46, 35359-35368, November 17, 2006

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The Role of a Novel p97/Valosin-containing Protein-interacting Motif of gp78 in Endoplasmic Reticulum-associated Degradation^*

Petek Ballar¹, Yuxian Shen^¶, Hui Yang, and Shengyun Fang²

From the Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201, ^¶The Institute of Clinical Pharmacology, Anhui Medical University, Hefei, P. R. China, and the Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201

Improperly folded proteins in the endoplasmic reticulum (ER) are eliminated via ER-associated degradation, a process that dislocates misfolded proteins from the ER membrane into the cytosol, where they undergo proteasomal degradation. Dislocation requires a subclass of ubiquitin ligases that includes gp78 in addition to the AAA ATPase p97/VCP and its cofactor, the Ufd1-Npl4 dimer. We have previously reported that gp78 interacts directly with p97/VCP. Here, we identify a novel p97/VCP-interacting motif (VIM) within gp78 that mediates this interaction. We demonstrate that the VIM of gp78 recruits p97/VCP to the ER, but has no effect on Ufd1 localization. We also show that gp78 VIM interacts with the ND1 domain of p97/VCP that was shown previously to be the binding site for Ufd1. To evaluate the role of Ufd1 in gp78-p97/VCP-mediated degradation of CD3, a known substrate of gp78, RNA interference was used to silence the expression of Ufd1 and p97/VCP. Inhibition of p97/VCP, but not Ufd1, stabilized CD3 in cells that overexpress gp78. However, both p97/VCP and Ufd1 appear to be required for CD3 degradation in cells expressing physiological levels of gp78. These results raise the possibility that Ufd1 and gp78 may bind p97/VCP in a mutually exclusive manner and suggest that gp78 might act in a Ufd1-independent degradation pathway for misfolded ER proteins, which operates in parallel with the previously established p97/VCP-Ufd1-Npl4-mediated mechanism.

Received for publication, April 7, 2006 , and in revised form, September 19, 2006.

^* 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 and S2.

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 Institute, UMBI Bldg., N359, 725 W. Lombard St., Baltimore, MD 21201. Tel.: 410-706-2220; Fax: 410-706-8184; E-mail: fangs{at}umbi.umd.edu.

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