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J. Biol. Chem., Vol. 280, Issue 2, 1634-1640, January 14, 2005

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Inositol Hexakisphosphate Kinase-2, a Physiologic Mediator of Cell Death^*

Eiichiro Nagata¶, Hongbo R. Luo¶||, Adolfo Saiardi, Byoung-Il Bae, Norihiro Suzuki, and Solomon H. Snyder**

From the Departments of Neuroscience, Pharmacology and Molecular Sciences, and Psychiatry, School of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205 and the Department of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

Diphosphoinositol pentakisphosphate (InsP7) and bis-diphosphoinositol tetrakisphosphate contain pyrophosphate bonds. InsP7 is formed from inositol hexakisphosphate (InsP6) by a family of three inositol hexakisphosphate kinases (InsP6K). In this study we establish one of the InsP6Ks, InsP6K2, as a physiologic mediator of cell death. Overexpression of wild-type InsP6K2 augments the cytotoxic actions of multiple cell stressors in diverse cell lines, whereas transfection with a dominant negative InsP6K2 decreases cell death. During cell death, InsP6 kinase activity is enhanced, and intracellular InsP7 level is augmented. Deletion of InsP6K2 but not the other forms of InsP6K diminishes cell death, suggesting that InsP6K2 is the major InsP6 kinase involved in cell death. Cytotoxicity is associated with a translocation of InsP6K2 from nuclei to mitochondria, whereas the intracellular localization of the other isoforms of the enzyme does not change. The present study provides compelling evidence that endogenous InsP6K2, by generating InsP7, provides physiologic regulation of the apoptotic process.

Received for publication, August 17, 2004 , and in revised form, November 4, 2004.

^* This work was funded by United States Public Health Service Grant MH-18501 and Research Scientist Grant DA-00074 (to S. 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.

^¶ These authors contributed equally to this work.

^|| Present address: Depts. of Pathology and Laboratory Medicine, Harvard Medical School and Children's Hospital Boston, Karp Bldg. 10214, 300 Longwood Ave., Boston, MA 02115.

^** To whom correspondence should be addressed: Tel.: 410-955-3024; Fax: 410-955-3623; E-mail: ssnyder{at}bs.jhmi.edu.

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