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Mol. Cell. Biol. doi:10.1128/MCB.01065-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

AIF IS A TARGET FOR UBIQUITINATION THROUGH INTERACTION WITH XIAP

Departments of Pathology, and Internal Medicine, University of Michigan, Ann Arbor, MI, 48109

^* To whom correspondence should be addressed. Email: colind{at}umich.edu.

	Abstract

X-linked inhibitor of apoptosis (XIAP) is an inhibitor of apoptotic cell death that protects cells by caspase-dependent and independent mechanisms. In a screen for molecules that participate with XIAP in regulating cellular activities, we identified AIF (apoptosis inducing factor) as an XIAP binding protein. BIR2 of XIAP is sufficient for the XIAP/AIF interaction, which is disrupted by Smac/DIABLO. In healthy cells, mature human AIF lacks only the first 54 amino acids, differing significantly from the apoptotic form which lacks the first 102 amino-terminal residues. Fluorescence complementation and immunoprecipitation experiments revealed that XIAP interacts with both AIF forms. AIF was found to be a target of XIAP-mediated ubiquitination under both normal and apoptotic conditions, and an E3 ubiquitin ligase deficient XIAP variant displayed a more robust interaction with AIF. Expression of either XIAP or AIF attenuated both basal and antimycin A stimulated levels of reactive oxygen species (ROS), and when expressed in combination, a cumulative decrease in ROS was observed. These results identify AIF as a new XIAP binding partner, and indicate a role for XIAP in regulating cellular ROS.

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