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* National Institute of Immunology, New Delhi, India;
National Centre for Biological Sciences, Bangalore, India; and
Department of Biological Sciences, University of Arkansas, Fayetteville, AR 72701
Apoptosis-inducing factor (Aif) is a mitochondrial flavoprotein with multiple roles in apoptosis as well as in cellular respiration and redox regulation. The harlequin (Hq) mouse strain carries an aif locus modification causing reduced Aif expression. We demonstrate that activated CD4+ and CD8+ peripheral T cells from Hq mice show resistance to neglect-induced death (NID) triggered by growth factor withdrawal, but not to death induced by multiple agents that trigger DNA damage. Aif translocates to the nucleus in cells undergoing NID, and, in Hq T cell blasts, resistance to NID is associated with reduced cytosolic release of mitochondrial cytochrome c, implicating Aif in this event. In contrast, Hq T cell blasts express higher levels of CD95L, demonstrating increased susceptibility to activation-induced cell death (AICD) and apoptosis triggered by hydrogen peroxide. Superoxide scavenging protects from AICD in wild-type, but not Hq, T cell blasts, suggesting that Aif plays a crucial superoxide-scavenging role to regulate T cell AICD. Finally, the altered pattern of death susceptibility is reproduced by siRNA-mediated reduction of Aif expression in normal T cells. Thus, Aif serves nonredundant roles, both proapoptotic and antiapoptotic, in activated peripheral T cells.
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 This work was supported in part by grants from the Department of Biotechnology and the Department of Science and Technology, Government of India (to A.G., S.R., and V.B.), the Indian Council of Medical Research, the Government of India (to V.B.), the National Institutes of Health (United States), and the Arkansas Biosciences Institute (to J.M.D.), the Arkansas Biotechnology Institute (to J.M.D.), and the Wellcome Trust (to V.B. and A.S.). National Institute of Immunology is supported by the Department of Biotechnology, Government of India.
2 H.B., A.C., and A.K. have contributed equally to this work.
3 A.S., A.G., V.B., J.M.D., and S.R. have contributed equally to this work.
4 Address correspondence and reprint requests to Dr. Satyajit Rath, National Institute of Immunology, Aruna Asaf Ali Road, New Delhi 110067, India. E-mail address: satyajit{at}nii.res.in
5 Abbreviations used in this paper: AICD, activation-induced cell death; cyt c, cytochrome c; Aif, apoptosis-inducing factor; ROS, reactive oxygen species; WT, wild type; AG, aminoguanidine; MnTBAP, Mn-tetrabenzoyl-aminoporphyrin; NID, neglect-induced death; siRNA, small-interfering RNA; SOD, superoxide dismutase; PTP, permeability transition pore; CsA, cyclosporine A; DR, death receptor.
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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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