[en] 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 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.
North, B. J., and Verdin, E. (2004) Genome Biol. 5, 224
Denu, J. M. (2005) Curr. Opin. Chem. Biol. 9, 431-440
Guarente, L. (2000) Genes Dev. 14, 1021-1026
Frye, R. A. (1999) Biochem. Biophys. Res. Commun. 260, 273-279
Frye, R. A. (2000) Biochem. Biophys. Res. Commun. 273, 793-798
Fulco, M., Schiltz, R. L., Iezzi, S., King, M. T., Zhao, P., Kashiwaya, Y., Hoffman, E., Veech, R. L., and Sartorelli, V. (2003) Mol. Cell 12, 51-62
Brunet, 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., and Greenberg, M. E. (2004) Science 303, 2011-2015
Vaziri, H., Dessain, S. K., Ng Eaton, E., Imai, S. I., Frye, R. A., Pandita, T. K., Guarente, L., and Weinberg, R. A. (2001) Cell 107, 149-159
Luo, J., Nikolaev, A. Y., Imai, S., Chen, D., Su, F., Shiloh, A., Guarente, L., and Gu, W. (2001) Cell 107, 137-148
Yeung, F., Hoberg, J. E., Ramsey, C. S., Keller, M. D., Jones, D. R., Frye, R. A., and Mayo, M. W. (2004) EMBO J. 23, 2369-2380
Langley, E., Pearson, M., Faretta, M., Bauer, U. M., Frye, R. A., Minucci, S., Pelicci, P. G., and Kouzarides, T. (2002) EMBO J. 21, 2383-2396
Motta, M. C., Divecha, N., Lemieux, M., Kamel, C., Chen, D., Gu, W., Bultsma, Y., McBurney, M., and Guarente, L. (2004) Cell 116, 551-563
North, B. J., Marshall, B. L., Borra, M. T., Denu, J. M., and Verdin, E. (2003) Mol. Cell 11, 437-444
Schwer, B., North, B. J., Frye, R. A., Ott, M., and Verdin, E. (2002) J. Cell Biol. 158, 647-657
Onyango, P., Celic, I., McCaffery, J. M., Boeke, J. D., and Feinberg, A. P. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 13653-13658
Min, J., Landry, J., Sternglanz, R., and Xu, R. M. (2001) Cell 105, 269-279
Avalos, J. L., Celic, I., Muhammad, S., Cosgrove, M. S., Boeke, J. D., and Wolberger, C. (2002) Mol. Cell 10, 523-535
Liszt, G., Ford, E., Kurtev, M., and Guarente, L. (2005) J. Biol. Chem. 280, 21313-21320
Garcia-Salcedo, J. A., Gijon, P., Nolan, D. P., Tebabi, P., and Pays, E. (2003) EMBO J. 22, 5851-5862
Merglen, A., Theander, S., Rubi, B., Chaffard, G., Wollheim, C. B., and Maechler, P. (2004) Endocrinology 145, 667-678
Asfari, M., Janjic, D., Meda, P., Li, G., Halban, P. A., and Wollheim, C. B. (1992) Endocrinology 130, 167-178
Graham, B. H., Waymire, K. G., Cottrell, B., Trounce, I. A., MacGregor, G. R., and Wallace, D. C. (1997) Nat. Genet. 16, 226-234
Farris, W., Mansourian, S., Chang, Y., Lindsley, L., Eckman, E. A., Frosch, M. P., Eckman, C. B., Tanzi, R. E., Selkoe, D. J., and Guenette, S. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 4162-4167
Miller, B. C., Eckman, E. A., Sambamurti, K., Dobbs, N., Chow, K. M., Eckman, C. B., Hersh, L. B., and Thiele, D. L. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 6221-6226
Kurochkin, I. V., and Goto, S. (1994) FEBS Lett. 345, 33-37
Leissring, M. A., Farris, W., Wu, X., Christodoulou, D. C., Haigis, M. C., Guarente, L., and Selkoe, D. J. (2004) Biochem. J. 383, 439-446
Pebay-Peyroula, E., and Brandolin, G. (2004) Curr. Opin. Struct. Biol. 14, 420-425
Shi, T., Wang, F., Stieren, E., and Tong, Q. (2005) J. Biol. Chem. 280, 13560-13567
Kennedy, E. D., Maechler, P., and Wollheim, C. B. (1998) Diabetes 47, 374-380
Chacinska, A., Pfanner, N., and Meisinger, C. (2002) Trends Cell Biol. 12, 299-303
Pfanner, N. (2000) Curr. Biol. 10, R412-R415
Roise, D., Theiler, F., Horvath, S. J., Tomich, J. M., Richards, J. H., Allison, D. S., and Schatz, G. (1988) EMBO J. 7, 649-653
Truscott, K. N., Brandner, K., and Pfanner, N. (2003) Curr. Biol. 13, R326-337
Luciano, P., and Geli, V. (1996) Experientia 52, 1077-1082
Michishita, E., Park, J. Y., Burneskis, J. M., Barrett, J. C., and Horikawa, I. (2005) Mol. Biol. Cell 16, 4623-4635
Hardy, D. L., and Mowbray, J. (1992) Biochem. J. 283, 849-854
Mowbray, J., and Hardy, D. L. (1996) FEBS Lett. 394, 61-65
Herrero-Yraola, A., Bakhit, S. M., Franke, P., Weise, C., Schweiger, M., Jorcke, D., and Ziegler, M. (2001) EMBO J. 20, 2404-2412
Maechler, P. (2003) Curr. Opin. Investig. Drugs 4, 1166-1172
Newgard, C. B., and McGarry, J. D. (1995) Annu. Rev. Biochem. 64, 689-719
Ashcroft, F. M., Proks, P., Smith, P. A., Ammala, C., Bokvist, K., and Rorsman, P. (1994) J. Cell Biochem. 55, (suppl.) 54-65
Lang, J. (1999) Eur. J. Biochem. 259, 3-17
Farris, W., Mansourian, S., Leissring, M. A., Eckman, E. A., Bertram, L., Eckman, C. B., Tanzi, R. E., and Selkoe, D. J. (2004) Am. J. Pathol. 164, 1425-1434
Bertram, L., Blacker, D., Mullin, K., Keeney, D., Jones, J., Basu, S., Yhu, S., McInnis, M. G., Go, R. C., Vekrellis, K., Selkoe, D. J., Saunders, A. J., and Tanzi, R. E. (2000) Science 290, 2302-2303
Fakhrai-Rad, H., Nikoshkov, A., Kamel, A., Fernstrom, M., Zierath, J. R., Norgren, S., Luthman, H., and Galli, J. (2000) Hum. Mol. Genet. 9, 2149-2158
Blander, G., and Guarente, L. (2004) Annu. Rev. Biochem. 73, 417-435
Tissenbaum, H. A., and Guarente, L. (2001) Nature 410, 227-230
Bordone, L., Motta, M. C., Picard, F., Robinson, A., Jhala, U. S., Apfeld, J., McDonagh, T., Lemieux, M., McBurney, M., Szilvasi, A., Easlon, E. J., Lin, S. J., and Guarente, L. (2006) PLoS Biol. 4, e31
Moynihan, K. A., Grimm, A. A., Plueger, M. M., Bernal-Mizrachi, E., Ford, E., Cras-Meneur, C., Permutt, M. A., and Imai, S. (2005) Cell Metab. 2, 105-117
Haigis, M. C., Mostoslavsky, R., Haigis, K. M., Fahie, K., Christodoulou, D. C., Murphy, A. J., Valenzuela, D. M., Yancopoulos, G. D., Karow, M., Blander, G., Wolberger, C., Prolla, T. A., Weindruch, R., Alt, F. W., and Guarente, L. (2006) Cell 126, 941-954
