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J. Biol. Chem., Vol. 282, Issue 28, 20104-20115, July 13, 2007

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SPFH2 Mediates the Endoplasmic Reticulum-associated Degradation of Inositol 1,4,5-Trisphosphate Receptors and Other Substrates in Mammalian Cells^*

Margaret M. P. Pearce, Yuan Wang, Grant G. Kelley, and Richard J. H. Wojcikiewicz¹

From the Departments of Pharmacology and Medicine, State University of New York Upstate Medical University, Syracuse, New York 13210

Inositol 1,4,5-trisphosphate (IP₃) receptors are endoplasmic reticulum (ER) membrane calcium channels that, upon activation, become substrates for the ER-associated degradation (ERAD) pathway. Although it is clear that IP₃ receptors are polyubiquitinated upon activation and are transferred to the proteasome by a p97-based complex, currently nothing is known about the proteins that initially select activated IP₃ receptors for ERAD. Here, we sought to identify novel proteins that associate with and mediate the ERAD of endogenous activated IP₃ receptors. SPFH2, an uncharacterized SPFH domain-containing protein, rapidly associated with IP₃ receptors in a manner that preceded significant polyubiquitination and the association of p97 and related proteins. SPFH2 was found to be an ER membrane protein largely residing within the ER lumen and in resting and stimulated cells was linked to ERAD pathway components, apparently via endogenous substrates undergoing degradation. Suppression of SPFH2 expression by RNA interference markedly inhibited IP₃ receptor polyubiquitination and degradation and the processing of other ERAD substrates. Overall, these studies identify SPFH2 as a key ERAD pathway component and suggest that it may act as a substrate recognition factor.

Received for publication, March 2, 2007 , and in revised form, April 25, 2007.

^* This work was supported by National Institutes of Health Grants DK49194 (to R. J. H. W.) and DK56294 (to G. G. K.) and by a Pharmaceutical Research and Manufacturers of America Foundation predoctoral fellowship (to M. M. P. P.). 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.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, State University of New York Upstate Medical University, 750 East Adams St., Syracuse, NY 13210. Tel.: 315-464-7956; Fax: 315-464-8014; E-mail: wojcikir{at}upstate.edu.

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