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J. Biol. Chem., Vol. 279, Issue 49, 51091-51099, December 3, 2004

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VIAF, a Conserved Inhibitor of Apoptosis (IAP)-interacting Factor That Modulates Caspase Activation^*

John C. Wilkinson, Bettina W. M. Richter¶||, Amanda S. Wilkinson, Ezra Burstein, Julie M. Rumble, Blerina Balliu, and Colin S. Duckett**

From the Departments of Pathology and ^**Internal Medicine, University of Michigan, Ann Arbor, Michigan, 48109 and the ^¶Metabolism Branch, Division of Clinical Sciences, NCI, National Institutes of Health, Bethesda, Maryland 20892-1578

Inhibitor of apoptosis (IAP) proteins are involved in the suppression of apoptosis, signal transduction, cell cycle control and gene regulation. Here we describe the cloning and characterization of viral IAP-associated factor (VIAF), a highly conserved, ubiquitously expressed phosphoprotein with limited homology to members of the phosducin family that associates with baculovirus Op-IAP. VIAF bound Op-IAP both in vitro and in intact cells, with each protein displaying a predominantly cytoplasmic localization. VIAF lacks a consensus IAP binding motif, and overexpression of VIAF failed to prevent Op-IAP from protecting human cells from a variety of apoptotic stimuli, suggesting that VIAF does not function as an IAP antagonist. VIAF was unable to directly inhibit caspase activation in vitro and a reduction of VIAF protein levels by RNA interference led to a decrease in Bax-mediated caspase activation, suggesting that VIAF functions to co-regulate the apoptotic cascade. Finally, VIAF is a substrate for ubiquitination mediated by Op-IAP. Thus, VIAF is a novel IAP-interacting factor that functions in caspase activation during apoptosis.

Received for publication, August 20, 2004 , and in revised form, September 10, 2004.

^* This work was supported in part by the University of Michigan Biomedical Scholars Program (to C. S. D.) and Grant T32 CA09676 (to J. C. W.) from the National Institutes of Health. 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.

This article is dedicated to Dr. Lois Miller.

These authors contributed equally to this work.

^|| Present address: Virion Systems, Inc., 9610 Medical Center Dr., ST100, Rockville, MD 20850.

To whom correspondence should be addressed: Med Sci I, Room 5315, 1301 Catherine St., Ann Arbor, MI 48109-0602. Tel.: 734-615-6414; Fax: 734-615-7012; E-mail: colind{at}umich.edu.

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				J. C. Wilkinson, A. S. Wilkinson, S. Galban, R. A. Csomos, and C. S. Duckett Apoptosis-Inducing Factor Is a Target for Ubiquitination through Interaction with XIAP Mol. Cell. Biol., January 1, 2008; 28(1): 237 - 247. [Abstract] [Full Text] [PDF]

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