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J. Biol. Chem., Vol. 282, Issue 46, 33583-33592, November 16, 2007

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Regulation of Insulin Secretion by SIRT4, a Mitochondrial ADP-ribosyltransferase^*

Nidhi Ahuja¹, Bjoern Schwer¹, Stefania Carobbio¹, David Waltregny^¶1, Brian J. North, Vincenzo Castronovo^¶, Pierre Maechler, and Eric Verdin, A Senior Scholar in Aging of the Ellison Medical Foundation²

From the Gladstone Institute of Virology and Immunology, University of California, San Francisco, California 94158, Department of Cell Physiology and Metabolism, University Medical Center, University of Geneva, CH-1211 Geneva 4, Switzerland, ^¶Metastasis Research Laboratory, University of Liege, B-4000 Liege, Belgium

Sirtuins are homologues of the yeast transcriptional repressor Sir2p and are conserved from bacteria to humans. We report that human SIRT4 is localized to the mitochondria. SIRT4 is a matrix protein and becomes cleaved at amino acid 28 after import into mitochondria. Mass spectrometry analysis of proteins that coimmunoprecipitate with SIRT4 identified insulindegrading enzyme and the ADP/ATP carrier proteins, ANT2 and ANT3. SIRT4 exhibits no histone deacetylase activity but functions as an efficient ADP-ribosyltransferase on histones and bovine serum albumin. SIRT4 is expressed in islets of Langerhans and colocalizes with insulin-expressing cells. Depletion of SIRT4 from insulin-producing INS-1E cells results in increased insulin secretion in response to glucose. These observations define a new role for mitochondrial SIRT4 in the regulation of insulin secretion.

Received for publication, July 5, 2007 , and in revised form, August 20, 2007.

^* This work was supported by funds from the J. David Gladstone Institutes (to E. V.), the Sandler Foundation at the University of California, San Francisco (to E. V.), the Ellison Medical Foundation (to E. V.), and the Swiss National Science Foundation (to P. M.). The UCSF Biomolecular Resource Center Mass Spectrometry facility was supported by a grant from the Sandler New Technology Fund. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental figures.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Gladstone Institute of Virology and Immunology/UCSF, 1650 Owens St., San Francisco, CA 94158. Tel.: 415-734-4808; Fax: 415-355-0855; E-mail: everdin{at}gladstone.ucsf.edu.

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