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, Eric Verdin

Research output: Contribution to journalArticlepeer-review

285 Scopus citations

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 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 β 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.

Original languageEnglish (US)
Pages (from-to)33583-33592
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number46
DOIs
StatePublished - Nov 16 2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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