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J. Biol. Chem., Vol. 281, Issue 12, 7873-7880, March 24, 2006

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Distinct hsp70 Domains Mediate Apoptosis-inducing Factor Release and Nuclear Accumulation^*

Kathleen Ruchalski¹, Haiping Mao¹, Zhijian Li, Zhiyong Wang, Sara Gillers, Yihan Wang^¶, Dick D. Mosser^||, Vladimir Gabai^**, John H. Schwartz, and Steven C. Borkan²

From the Department of Nephrology, First Affiliated Hospital, Zhongshan University, GuangZhou, China, Renal Section, Department of Medicine, Boston Medical Center, Boston University, Boston, Massachusetts 02118-2518, ^¶Department of Pathology, Vanderbilt University, Nashville, Tennessee 37232-2561, ^||Department of Molecular Biology and Genetics, University of Guelph, Ontario N1G 2W1, Canada, ^**Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118

Although hsp70 antagonizes apoptosis-inducing factor (AIF)-mediated cell death, the relative importance of preventing its release from mitochondria versus sequestering leaked AIF in the cytosol remains controversial. To dissect these two protective mechanisms, hsp70 deletion mutants lacking either the chaperone function (hsp70-EEVD) or ATPase function (hsp70-ATPase) were selectively overexpressed before exposing cells to a metabolic inhibitor, an insult sufficient to cause mitochondrial AIF release, nuclear AIF accumulation, and apoptosis. Compared with empty vector, overexpression of wild type human hsp70 inhibited bax activation and reduced mitochondrial AIF release after injury. In contrast, mutants lacking either the chaperone function (hsp70-EEVD) or the ATP hydrolytic domain (hsp70-ATPase) failed to prevent mitochondrial AIF release. Although hsp70-EEVD did not inhibit bax activation or mitochondrial membrane injury after cell stress, this hsp70 mutant co-immunoprecipitated with leaked AIF in injured cells and decreased nuclear AIF accumulation. In contrast, hsp70-ATPase did not interact with AIF either in intact cells or in a cell-free system and furthermore, failed to prevent nuclear AIF accumulation. These results demonstrate that mitochondrial protection against bax-mediated injury requires both intact chaperone and ATPase functions, whereas the ATPase domain is critical for sequestering AIF in the cytosol.

Received for publication, December 27, 2005

^* This work was supported by National Institutes of Health Grants DK-53387 (to S. C. B.) and DK-52898 (to J. H. S.). 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 Both authors contributed equally to the preparation of this manuscript.

² To whom correspondence should be addressed: Evans Biomedical Research Center, Renal Section, Rm. 546, 650 Albany St., Boston, MA 02118-2518. Tel.: 617-638-7330; Fax: 617-638-7326; E-mail: sborkan{at}bu.edu.

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