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Molecular and Cellular Biology, January 2008, p. 237-247, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01065-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Apoptosis-Inducing Factor Is a Target for Ubiquitination through Interaction with XIAP{triangledown} ,{dagger}

John C. Wilkinson,1,{ddagger} Amanda S. Wilkinson,1,{ddagger} Stefanie Galbán,1 Rebecca A. Csomos,1 and Colin S. Duckett1,2*

Departments of Pathology,1 Internal Medicine, University of Michigan, Ann Arbor, Michigan 481092

Received 15 June 2007/ Returned for modification 19 July 2007/ Accepted 8 October 2007

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 apoptosis-inducing factor (AIF) as an XIAP binding protein. Baculoviral IAP repeat 2 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 XIAP and AIF were 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.

* Corresponding author. Mailing address: BSRB, Room 2057, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200. Phone: (734) 615-6414. Fax: (734) 763-2162. E-mail: colind{at}umich.edu

{triangledown} Published ahead of print on 29 October 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Department of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157.

Molecular and Cellular Biology, January 2008, p. 237-247, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01065-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Churbanova, I. Y., Sevrioukova, I. F. (2008). Redox-dependent Changes in Molecular Properties of Mitochondrial Apoptosis-inducing Factor. J. Biol. Chem. 283: 5622-5631 [Abstract] [Full Text]  


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