Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase

doi:10.1074/jbc.M705488200

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Papers In Press, published online ahead of print August 22, 2007
J. Biol. Chem, 10.1074/jbc.M705488200
Submitted on July 5, 2007
Revised on August 20, 2007
Accepted on August 22, 2007

Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase

Nidhi Ahuja, Bjoern Schwer, Stefania Carobbio, David Waltregny, Brian J. North, Vincenzo Castronovo, Pierre Maechler, and Eric Verdin

Laboratory of Molecular Virology, Gladstone Institute of Virology and Immunology, San Francisco, CA 94158

Corresponding Author: everdin{at}gladstone.ucsf.edu

Sirtuins are homologues of the yeast transcriptional repressor Sir2p and are conserved from bacteria to hu-mans. 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 mito-chondria. Mass spectrometry analysis of proteins that coimmunoprecipitate with SIRT4 identified insulin-degrading 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 b 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.

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