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

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 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.

[1]  J. Lang.  Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion. , 1999, European journal of biochemistry.

[2]  J. Mowbray,et al.  Direct thyroid hormone signalling via ADP‐ribosylation controls mitochondrial nucleotide transport and membrane leakiness by changing the conformation of the adenine nucleotide transporter , 1996, FEBS letters.

[3]  J. Denu,et al.  The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. , 2003, Molecular cell.

[4]  D. Selkoe,et al.  Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein. , 2004, The American journal of pathology.

[5]  Madeleine Lemieux,et al.  Sirt1 Regulates Insulin Secretion by Repressing UCP2 in Pancreatic β Cells , 2005, PLoS biology.

[6]  L. Guarente,et al.  Mouse Sir2 Homolog SIRT6 Is a Nuclear ADP-ribosyltransferase* , 2005, Journal of Biological Chemistry.

[7]  L. Hersh,et al.  Amyloid-β peptide levels in brain are inversely correlated with insulysin activity levels in vivo , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[8]  R. Sternglanz,et al.  Crystal Structure of a SIR2 Homolog–NAD Complex , 2001, Cell.

[9]  Delin Chen,et al.  Negative Control of p53 by Sir2α Promotes Cell Survival under Stress , 2001, Cell.

[10]  H. Luthman,et al.  Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats. , 2000, Human molecular genetics.

[11]  M. Saraste,et al.  FEBS Lett , 2000 .

[12]  E. Verdin,et al.  Sirtuins: Sir2-related NAD-dependent protein deacetylases , 2004, Genome Biology.

[13]  N. Pfanner,et al.  Mechanisms of Protein Import into Mitochondria , 2003, Current Biology.

[14]  F. Ashcroft,et al.  Stimulus–secretion coupling in pancreatic β cells , 1994 .

[15]  S. Theander,et al.  Glucose sensitivity and metabolism-secretion coupling studied during two-year continuous culture in INS-1E insulinoma cells. , 2004, Endocrinology.

[16]  R. Weinberg,et al.  hSIR2SIRT1 Functions as an NAD-Dependent p53 Deacetylase , 2001, Cell.

[17]  F. Alt,et al.  SIRT4 Inhibits Glutamate Dehydrogenase and Opposes the Effects of Calorie Restriction in Pancreatic β Cells , 2006, Cell.

[18]  S. Minucci,et al.  Human SIR2 deacetylates p53 and antagonizes PML/p53‐induced cellular senescence , 2002, The EMBO journal.

[19]  R. Rosenfeld.  Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[20]  C. Newgard,et al.  Metabolic coupling factors in pancreatic beta-cell signal transduction. , 1995, Annual review of biochemistry.

[21]  I. Kurochkin,et al.  Alzheimer's β‐amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme , 1994, FEBS letters.

[22]  Izumi Horikawa,et al.  Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. , 2005, Molecular biology of the cell.

[23]  P. Maechler.  Novel regulation of insulin secretion: the role of mitochondria. , 2003, Current opinion in investigational drugs.

[24]  M G McInnis,et al.  Evidence for genetic linkage of Alzheimer's disease to chromosome 10q. , 2000, Science.

[25]  E. Verdin,et al.  The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide–dependent deacetylase , 2002, The Journal of cell biology.

[26]  L. Guarente,et al.  The Sir2 family of protein deacetylases. , 2004, Annual review of biochemistry.

[27]  E. Pebay-Peyroula,et al.  Nucleotide exchange in mitochondria: insight at a molecular level. , 2004, Current opinion in structural biology.

[28]  Po Zhao,et al.  Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state. , 2003, Molecular cell.

[29]  J. Denu.  The Sir 2 family of protein deacetylases. , 2005, Current opinion in chemical biology.

[30]  N. Pfanner,et al.  How mitochondria import hydrophilic and hydrophobic proteins. , 2002, Trends in cell biology.

[31]  J. Richards,et al.  Amphiphilicity is essential for mitochondrial presequence function. , 1988, The EMBO journal.

[32]  M. Ziegler,et al.  Regulation of glutamate dehydrogenase by reversible ADP‐ribosylation in mitochondria , 2001, The EMBO journal.

[33]  N. Pfanner.  Protein sorting: Recognizing mitochondrial presequences , 2000, Current Biology.

[34]  D. Nolan,et al.  A chromosomal SIR2 homologue with both histone NAD‐dependent ADP‐ribosyltransferase and deacetylase activities is involved in DNA repair in Trypanosoma brucei , 2003, The EMBO journal.

[35]  R. Frye,et al.  Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. , 1999, Biochemical and biophysical research communications.

[36]  A. Feinberg,et al.  SIRT3, a human SIR2 homologue, is an NAD- dependent deacetylase localized to mitochondria , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[37]  V. Géli,et al.  The mitochondrial processing peptidase: Function and specificity , 1996, Experientia.

[38]  Delin Chen,et al.  Mammalian SIRT1 Represses Forkhead Transcription Factors , 2004, Cell.

[39]  Matthew P. Frosch,et al.  Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[40]  L. Guarente,et al.  Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans , 2001, Nature.

[41]  D. Wallace,et al.  A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator , 1997, Nature Genetics.

[42]  Q. Tong,et al.  SIRT3, a Mitochondrial Sirtuin Deacetylase, Regulates Mitochondrial Function and Thermogenesis in Brown Adipocytes* , 2005, Journal of Biological Chemistry.

[43]  L. Guarente,et al.  Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondria. , 2004, The Biochemical journal.

[44]  宁北芳,et al.  疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A , 2005 .

[45]  M. Permutt,et al.  Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. , 2005, Cell metabolism.

[46]  L. Guarente,et al.  Sir2 links chromatin silencing, metabolism, and aging. , 2000, Genes & development.

[47]  M. Mayo,et al.  Modulation of NF‐κB‐dependent transcription and cell survival by the SIRT1 deacetylase , 2004, The EMBO journal.

[48]  Jef D. Boeke,et al.  Structure of a Sir2 enzyme bound to an acetylated p53 peptide. , 2002, Molecular cell.

[49]  C. Wollheim,et al.  Effects of depletion of mitochondrial DNA in metabolism secretion coupling in INS-1 cells. , 1998, Diabetes.

[50]  R. Frye,et al.  Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. , 2000, Biochemical and biophysical research communications.

[51]  Steven P. Gygi,et al.  Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase , 2004, Science.