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

  • J Biol Chem. 2007 Nov 16;282(46):33583-33592. doi: 10.1074/jbc.M705488200.
Nidhi Ahuja  1 ,  Bjoern Schwer  1 ,  Stefania Carobbio  2 ,  David Waltregny  3 ,  Brian J North  1 ,  Vincenzo Castronovo  3 ,  Pierre Maechler  2 ,  Eric Verdin  4
Affiliations
  • 1. Gladstone Institute of Virology and Immunology, University of California, San Francisco, California 94158.
  • 2. Department of Cell Physiology and Metabolism, University Medical Center, University of Geneva, CH-1211 Geneva 4, Switzerland.
  • 3. Metastasis Research Laboratory, University of Liege, B-4000 Liege, Belgium.
  • 4. Gladstone Institute of Virology and Immunology, University of California, San Francisco, California 94158. Electronic address: [email protected].
PMID: 17715127 DOI: 10.1074/jbc.M705488200
Abstract

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 beta 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.