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M513728200v1
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Papers In Press, published online ahead of print January 4, 2006
J. Biol. Chem, 10.1074/jbc.M513728200
Submitted on December 27, 2005
Accepted on January 4, 2006

Distinct Hsp70 domains mediate apoptosis inducing factor release and nuclear accumulation

Kathleen L Ruchalski, Haiping Mao, Zhijian Li, Zhiyong Wang, Sara Gillers, Yihan Wang, Dick D Mosser, Vladimir Gabai, John H Schwartz, and Steen C Borkan

Renal Section, Boston Medical Center, Boston, MA 02118-2518

Corresponding Author: sborkan{at}bu.edu

Although hsp70 antagonizes apoptosis inducing factor (AIF)-mediated cell death, the relative importance of preventing its release from mitochondria vs. 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 over-expressed before exposing cells to a metabolic inhibitor, an insult sufficient to cause mitochondrial AIF release, nuclear AIF accumulation and apoptosis. Compared to empty vector, over-expression of wild type human hsp70 (wt-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-immuno-precipitated 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.


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