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. 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. Histone deacetylases are enzymes that catalyze the removal of acetyl groups from the ϵ-amino group of lysine residues and are separated into three classes. Sirtuins, the class III histone deacetylases, are homologous to the yeast transcriptional repressor, Sir2p, and are NAD+-dependent enzymes (1North B.J. Verdin E. Genome Biol. 2004; 5: 224Crossref PubMed Scopus (438) Google Scholar, 2Denu J.M. Curr. Opin. Chem. Biol. 2005; 9: 431-440Crossref PubMed Scopus (230) Google Scholar, 3Guarente L. Genes Dev. 2000; 14: 1021-1026Crossref PubMed Google Scholar). Seven sirtuins have been identified in the human genome (4Frye R.A. Biochem. Biophys. Res. Commun. 1999; 260: 273-279Crossref PubMed Scopus (665) Google Scholar, 5Frye R.A. Biochem. Biophys. Res. Commun. 2000; 273: 793-798Crossref PubMed Scopus (1153) Google Scholar). They share a conserved Sir2 catalytic core domain and exhibit variable amino- and carboxyl-terminal extensions that contribute to their unique subcellular localization and may also regulate their catalytic activity. The subcellular distribution, substrate specificity, and cellular functions of sirtuins are quite diverse (reviewed in Refs. 1North B.J. Verdin E. Genome Biol. 2004; 5: 224Crossref PubMed Scopus (438) Google Scholar, 2Denu J.M. Curr. Opin. Chem. Biol. 2005; 9: 431-440Crossref PubMed Scopus (230) Google Scholar, 3Guarente L. Genes Dev. 2000; 14: 1021-1026Crossref PubMed Google Scholar). SIRT1 is found in the nucleus, where it functions as a transcriptional repressor via histone deacetylation. SIRT1 can also regulate transcription by modifying the acetylation levels of transcription factors, such as MyoD, FOXO, p53, and NF-κB (6Fulco M. Schiltz R.L. Iezzi S. King M.T. Zhao P. Kashiwaya Y. Hoffman E. Veech R.L. Sartorelli V. Mol. Cell. 2003; 12: 51-62Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar, 7Brunet A. Sweeney L.B. Sturgill J.F. Chua K.F. Greer P.L. Lin Y. Tran H. Ross S.E. Mostoslavsky R. Cohen H.Y. Hu L.S. Cheng H.L. Jedrychowski M.P. Gygi S.P. Sinclair D.A. Alt F.W. Greenberg M.E. Science. 2004; 303: 2011-2015Crossref PubMed Scopus (2634) Google Scholar, 8Vaziri H. Dessain S.K. Ng Eaton E. Imai S.I. Frye R.A. Pandita T.K. Guarente L. Weinberg R.A. Cell. 2001; 107: 149-159Abstract Full Text Full Text PDF PubMed Scopus (2288) Google Scholar, 9Luo J. Nikolaev A.Y. Imai S. Chen D. Su F. Shiloh A. Guarente L. Gu W. Cell. 2001; 107: 137-148Abstract Full Text Full Text PDF PubMed Scopus (1884) Google Scholar, 10Yeung F. Hoberg J.E. Ramsey C.S. Keller M.D. Jones D.R. Frye R.A. Mayo M.W. EMBO J. 2004; 23: 2369-2380Crossref PubMed Scopus (2186) Google Scholar, 11Langley E. Pearson M. Faretta M. Bauer U.M. Frye R.A. Minucci S. Pelicci P.G. Kouzarides T. EMBO J. 2002; 21: 2383-2396Crossref PubMed Scopus (753) Google Scholar, 12Motta M.C. Divecha N. Lemieux M. Kamel C. Chen D. Gu W. Bultsma Y. McBurney M. Guarente L. Cell. 2004; 116: 551-563Abstract Full Text Full Text PDF PubMed Scopus (1192) Google Scholar). The SIRT2 protein is found in the cytoplasm, where it associates with microtubules and deacetylates lysine 40 of α-tubulin (13North B.J. Marshall B.L. Borra M.T. Denu J.M. Verdin E. Mol. Cell. 2003; 11: 437-444Abstract Full Text Full Text PDF PubMed Scopus (1232) Google Scholar). The SIRT3 protein is localized in the mitochondrial matrix (14Schwer B. North B.J. Frye R.A. Ott M. Verdin E. J. Cell Biol. 2002; 158: 647-657Crossref PubMed Scopus (456) Google Scholar, 15Onyango P. Celic I. McCaffery J.M. Boeke J.D. Feinberg A.P. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 13653-13658Crossref PubMed Scopus (435) Google Scholar), where it is proteolytically processed at its NH2 terminus, yielding a mature protein that has protein deacetylase activity (14Schwer B. North B.J. Frye R.A. Ott M. Verdin E. J. Cell Biol. 2002; 158: 647-657Crossref PubMed Scopus (456) Google Scholar). These observations indicate that the targets of sirtuins are not restricted to histone proteins but extend to acetylated proteins in other subcellular compartments. Sirtuins also differ in their substrate specificities. For instance, SIRT1, -2, and -3 have robust activity on chemically acetylated histone H4 peptides, whereas SIRT5 has weak but detectable activity, and SIRT4, -6, and -7 have no detectable activity on the same substrate (13North B.J. Marshall B.L. Borra M.T. Denu J.M. Verdin E. Mol. Cell. 2003; 11: 437-444Abstract Full Text Full Text PDF PubMed Scopus (1232) Google Scholar). Interestingly, a sirtuin from Archaeoglobus fulgidus, Sir2-Af1, which has close homology with SIRT5, also has weak activity on a histone peptide but significantly stronger activity on an acetylated bovine serum albumin substrate (16Min J. Landry J. Sternglanz R. Xu R.M. Cell. 2001; 105: 269-279Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, 17Avalos J.L. Celic I. Muhammad S. Cosgrove M.S. Boeke J.D. Wolberger C. Mol. Cell. 2002; 10: 523-535Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar). Similarly, both SIRT1 and SIRT2 can deacetylate p53; however, only SIRT2 deacetylates lysine 40 of α-tubulin (13North B.J. Marshall B.L. Borra M.T. Denu J.M. Verdin E. Mol. Cell. 2003; 11: 437-444Abstract Full Text Full Text PDF PubMed Scopus (1232) Google Scholar, 17Avalos J.L. Celic I. Muhammad S. Cosgrove M.S. Boeke J.D. Wolberger C. Mol. Cell. 2002; 10: 523-535Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar). Recently, SIRT6 was demonstrated to be a nuclear ADP-ribosyltransferase (18Liszt G. Ford E. Kurtev M. Guarente L. J. Biol. Chem. 2005; 280: 21313-21320Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar), whereas a T. brucei SIR2 homologue exhibited both histone NAD-dependent ADP-ribosyltransferase and deacetylase activities (19Garcia-Salcedo J.A. Gijon P. Nolan D.P. Tebabi P. Pays E. EMBO J. 2003; 22: 5851-5862Crossref PubMed Scopus (110) Google Scholar). These observations indicate that sirtuins can function either as NAD-dependent protein deacetylases or as ribosyltransferases. The substrate specificities of SIRT3 to -7 are unknown. Determining the localization patterns of these proteins is the first step in elucidating the physiologically relevant targets for deacetylation by each of these enzymes. Here, we report that SIRT4 is targeted to the mitochondrial matrix, where it interacts with insulin-degrading enzyme and the ADP/ATP carrier protein. Depletion of SIRT4 from insulin producing INS-1E cells results in increase in secretion of insulin from these cells in response to glucose, suggesting that SIRT4 negatively regulates insulin secretion in these cells. Tissue Culture—HEK293, HEK293T and HeLa cells were grown in Dulbeccoʼns modified Eagleʼns medium (Invitrogen) supplemented with 10% fetal bovine serum (Gemini Bio-products, Woodland, CA) in the presence of penicillin, streptomycin, and The β INS-1E A. S. B. G. P. 2004; PubMed Scopus Google Scholar), from cells M. D. P. G. PubMed Scopus Google Scholar), was grown in medium supplemented with fetal penicillin, streptomycin, and of INS-1E cells were with insulin-degrading bovine serum or SIRT4 by and in medium for and human SIRT4 was in a of to the as (13North B.J. Marshall B.L. Borra M.T. Denu J.M. Verdin E. Mol. Cell. 2003; 11: 437-444Abstract Full Text Full Text PDF PubMed Scopus (1232) Google Scholar). of SIRT4 were by The CA) was for were enzyme and SIRT4 was in a peptide to the amino of SIRT4 was by C. of and as B. PubMed Scopus Google Scholar). and cells grown on were with of the cells were with and with Dulbeccoʼns modified Eagleʼns medium 40 for at in and with Dulbeccoʼns modified Eagleʼns medium for The cells were in for at with for and with bovine serum albumin for was with for by with a for The cells were with and with The were on and by with an with a cells were by and in were removal of and cells by at for the was by at for The was at for to the from the proteins The and the were in and the protein was with protein of protein from each were to and by and cells were by the and after were by as and in in the presence of a was with for at from was three for each with and in from HEK293T cells were in and in three were by and in or The were on for and with on for was with and proteins were in by with and by were from HEK293T cells and in for at were at for at by in proteins were by in and by were from cells in and with a three for The was at for at to the from the cells were in in the presence of a and was with for at from was three for each with and by with peptide The of or histone proteins and the and The was by of and SIRT4 and the was to for at was from the were with and separated on after for The were and was of Cell and or was with the enzyme and into cells. of the cells were in medium SIRT4 and Mass were and in in the presence of a and was with at from was three for each with and in The were to by to proteins with SIRT4 were and for were in were with of the was was and the were in a were by with for at The was and the were in for in at in for the were with for and in a of were to the by on for was to the for at the was to a and were by the for in and peptide were and were by of each peptide with of matrix acid in on a of the peptide with the matrix, peptide were a the were a with a that the at a of of the peptide of the into the after a peptide were separated to their as the the the peptide were by the it each to the from its to the of peptide from the in with the of the the for the of each peptide to be of their was by the of peptide with of from each protein in the on the by a of were the Mass to the on the and cells or a were in cells were with in and in for on were and with for at were with and by of SIRT4 protein in human was on human the and the SIRT4 a peptide of amino of human SIRT4 was of were in and in of activity with in for the were with serum in for was at by and the were three with after each activity was by a of in and The was and to the for was to the by and were with of the first in the of insulin by the β cells of the islets of Langerhans was on of human the and a at a of from from and by L. W. of on human or on a of human of the were with a with a to the SIRT4 were as and were chemically by of SIRT4 for and for were (Invitrogen) in to the INS-1E cells were into the of were for with in to cells. cells were with the for in the medium cells were in for to and were in INS-1E and was by was of SIRT4 cells in were with after was the and was into for SIRT4 and were the was an and were the core The were to the of SIRT4 were as were as of protein of INS-1E cells was on were and at in the presence of human SIRT4 The was for with to and the SIRT4 protein was by cells in were with or and after for insulin secretion as A. S. B. G. P. 2004; PubMed Scopus Google Scholar). to the cells were for in and The cells were and in supplemented with bovine serum albumin as the at at and and with the mitochondrial substrate as as in the presence as a the of the were and for insulin and insulin was from cells in to insulin levels were by insulin as and secretion was expressed to cellular protein levels were in INS-1E cells the with the cells were with the of and for were with of and for at at glucose. was and the was in the A. S. B. G. P. 2004; PubMed Scopus Google Scholar). the results were expressed as groups were by for and was by a of SIRT4 a the subcellular localization of human SIRT4, HeLa cells were with a analysis of the cells by that was localized in in the that were of The of with a that in the mitochondrial localization of SIRT4 in the HeLa cells the subcellular localization of SIRT4, HEK293T cells the protein were by in a a and into a protein analysis that SIRT4 was localized in the The of these was by for the mitochondrial and the SIRT4 is also localized to the a was a peptide to the amino of human The with a protein in the of HEK293T cells SIRT4 at NH2 human SIRT4 a protein with a of both and SIRT4 in the on with an of is with the that SIRT4 is proteolytically as for mitochondrial The to SIRT4 was its and the of SIRT4, suggesting that at the NH2 for at the was in HEK293T from mitochondrial and to by analysis that the first 28 amino of SIRT4 are from the mature of the protein in the of SIRT4 the first 28 residues after that the 28 residues of SIRT4 are for of SIRT4 to the and that the of SIRT4 after the protein the mitochondria. We also a of of SIRT4 for mitochondrial localization and that of the first amino of SIRT4 mitochondrial not SIRT4 in the can be the the the and the the localization of SIRT4, were with to proteins and proteins with the SIRT4 was these that it is not with the and is the mitochondrial and were also to the these of with proteins to as which of their and were by of in to the of with of an whereas the matrix protein was as SIRT4 was to in that SIRT4 be in the to the of the or as a protein in the mitochondrial these of the was proteins are and separated from proteins after the mitochondrial matrix was found in the whereas the was in the SIRT4 was found in the that it in the mitochondrial matrix, either as a protein or with the of the mitochondrial these were in a proteins were separated from proteins by analysis of these that SIRT4 was as a protein These results indicate that SIRT4 is a mitochondrial matrix protein. SIRT4 with ADP-ribosyltransferase have that SIRT4 exhibited no histone deacetylase activity on a histone peptide (13North B.J. Marshall B.L. Borra M.T. Denu J.M. Verdin E. Mol. Cell. 2003; 11: 437-444Abstract Full Text Full Text PDF PubMed Scopus (1232) Google Scholar). were to a protein deacetylase activity with These the and of SIRT4 in and the of other a modified substrate These were and no protein deacetylase activity be identified in with SIRT4 not also no detectable protein deacetylase activity (13North B.J. Marshall B.L. Borra M.T. Denu J.M. Verdin E. Mol. Cell. 2003; 11: 437-444Abstract Full Text Full Text PDF PubMed Scopus (1232) Google and was demonstrated to function as an ADP-ribosyltransferase (18Liszt G. Ford E. Kurtev M. Guarente L. J. Biol. Chem. 2005; 280: 21313-21320Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar). the that SIRT4 also exhibit ADP-ribosyltransferase activity, we or the from cells after and the either with histone proteins or with in the presence of that SIRT4 the of histone proteins to a of as a of histones and was the SIRT4 was in these of by Mass proteins, we first a and a the These cells were and and was The was at to proteins and in analysis three of and These were with SIRT4 and not from the not These were from the and to spectrometry The was identified as insulin-degrading enzyme unique were identified the of with a of of the is a that regulates β peptide levels and insulin levels in W. S. Y. L. M.P. S. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar, N. L.B. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar, S. PubMed Scopus Google Scholar). of at an of the results in the of a acid mitochondrial and to the mitochondrial localization of a of the cellular W. M.C. Guarente L. Biochem. J. 2004; PubMed Scopus Google Scholar). The was a of proteins that not results not The ANT2 and also ANT3. ANT2 and and were to of ANT2 and in and and are mitochondrial proteins that catalyze the of in the by in the E. G. Curr. Opin. Biol. 2004; 14: PubMed Scopus Google Scholar). SIRT4 with and the SIRT4 and or we from cells either or were with an The was by for or We that with matrix mitochondrial sirtuin (14Schwer B. North B.J. Frye R.A. Ott M. Verdin E. J. Cell Biol. 2002; 158: 647-657Crossref PubMed Scopus (456) Google Scholar), also with These were not with either or SIRT3 the same expressed at a in these cells analysis demonstrated the presence of of or SIRT3 in the for the same we also found that ANT2 with of the demonstrated that of ANT2 were expressed in the for SIRT4 in a of and Cell the β of the of have been in human by and T. F. E. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar). We and a SIRT4 to SIRT4 protein levels in human We SIRT4 in cells and with a localization weak but detectable of SIRT4 was in whereas was in islets of Langerhans with an on that SIRT4 is expressed by insulin-producing β cells the The of was by the no on human on human on human and on a of human of SIRT4 via in β of SIRT4 in β cells in the and its with and proteins that insulin that SIRT4 regulate insulin secretion. SIRT4 was from an insulin-producing and insulin secretion in response to was of SIRT4 by to a in SIRT4 in INS-1E cells and to a at the protein as by secretion in the of these cells was and INS-1E cells with the insulin secretion was by in with glucose. The a no in or in the response to response was in with cells with the insulin secretion was by SIRT4 was cellular insulin were not significantly by SIRT4 of of SIRT4 not insulin secretion. at insulin secretion was increased in cells of SIRT4 insulin secretion was with a mitochondrial no in insulin secretion was in INS-1E cells with the role of SIRT4 in insulin secretion via its activity in we also a of insulin secretion after of INS-1E cells with a that is by P. PubMed Scopus Google Scholar). that insulin secretion was significantly SIRT4 was via on these SIRT4 at the of by modifying we in INS-1E in which SIRT4 has been via in was cells with a with with an a not the that in at the at a of close the and at the SIRT4 in β the role of SIRT4 in insulin we INS-1E cells with an for analysis SIRT4 a of SIRT4 after of the SIRT4 in with the of insulin secretion the same that of SIRT4 was with a of insulin secretion in response to These observations the role of SIRT4 in insulin secretion in response to glucose. in cells is a by a of for the subcellular such as nucleus, and have their of mitochondrial proteins are by nuclear and are as on after which are into the A. N. C. Cell Biol. 2002; 12: Full Text Full Text PDF PubMed Scopus Google Scholar). that SIRT4 is localized in the of cells. The subcellular localization of SIRT4 was both by and an SIRT4 the protein. a of and of we that SIRT4 in the mitochondrial matrix as a protein. are into A. N. C. Cell Biol. 2002; 12: Full Text Full Text PDF PubMed Scopus Google Scholar). The class mitochondrial proteins with extensions or of amino that are in and residues and have a to an with and N. Curr. Biol. 2000; 10: Full Text Full Text PDF PubMed Scopus Google Scholar, D. F. J.M. G. EMBO J. PubMed Scopus Google Scholar). The function as that with the mitochondrial import and the both the and N. Curr. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The class has that are the of the proteins and are not in amino A. N. C. Cell Biol. 2002; 12: Full Text Full Text PDF PubMed Scopus Google Scholar). observations indicate that SIRT4 as a mitochondrial matrix protein. of the SIRT4 protein in the mitochondrial matrix that it is the first 28 amino by the of by mitochondrial is for matrix proteins after import into the P. V. PubMed Scopus Google Scholar). SIRT4 is as a protein with a acid peptide that is for to the mitochondria. of a SIRT4 the first or 28 residues that the proteins are the and are not targeted to the mitochondria. of SIRT4 also identified residues as a to an analysis of that mitochondrial of SIRT4 is the of is by residues with B. S. D. B. J. V. P. and E. the residues and of SIRT4 to mitochondrial of SIRT4 and is from the with these E. J.M. I. Mol. Biol. Cell. 2005; PubMed Scopus Google also that human SIRT4 and SIRT5 to with the mitochondrial a of and we have not deacetylase activity with the SIRT4 protein. we have that SIRT4 is with a and ADP-ribosyltransferase activity. was for SIRT6 (18Liszt G. Ford E. Kurtev M. Guarente L. J. Biol. Chem. 2005; 280: 21313-21320Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar). 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PubMed Scopus Google Scholar, E. Ford E. C. Imai S. Cell 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). that SIRT1 regulates insulin secretion in β in by the of the mitochondrial protein protein that may new observations of to by a SIRT4, as a protein that negatively regulates insulin secretion. M.C. Mostoslavsky R. M. G. Wolberger C. R. Alt F.W. Guarente L. Cell. Full Text Full Text PDF PubMed Scopus Google also that SIRT4 is a mitochondrial protein and insulin secretion. They identified as a for SIRT4 activity and that SIRT4 the of in β cells M.C. Mostoslavsky R. M. G. Wolberger C. R. Alt F.W. Guarente L. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). results are to these targets for SIRT4 and and the role of SIRT4 in the of insulin secretion in β cells. in either SIRT1 or SIRT4 be to in a the role of sirtuins in insulin secretion and We and for and for We C. and H. from the of Mass We of of for the in the and of for the ANT2 with