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 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.
Ahuja
Nidhi
N
Gladstone Institute of Virology and Immunology, University of California, San Francisco, California 94158.
Schwer
Bjoern
B
Gladstone Institute of Virology and Immunology, University of California, San Francisco, California 94158.
Carobbio
Stefania
S
Department of Cell Physiology and Metabolism, University Medical Center, University of Geneva, CH-1211 Geneva 4, Switzerland.
Waltregny
David
D
Metastasis Research Laboratory, University of Liege, B-4000 Liege, Belgium.
North
Brian J
BJ
Gladstone Institute of Virology and Immunology, University of California, San Francisco, California 94158.
Castronovo
Vincenzo
V
Metastasis Research Laboratory, University of Liege, B-4000 Liege, Belgium.
Maechler
Pierre
P
Department of Cell Physiology and Metabolism, University Medical Center, University of Geneva, CH-1211 Geneva 4, Switzerland.
Verdin
Eric
E
Gladstone Institute of Virology and Immunology, University of California, San Francisco, California 94158. Electronic address: everdin@gladstone.ucsf.edu.
D036002:ADP Ribose Transferases / Q000737:chemistry*; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D013058:Mass Spectrometry; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins; D010957:Plasmids / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D037761:Sirtuins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D014162:Transfection
D018076:DNA, Complementary; D007328:Insulin; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D036002:ADP Ribose Transferases; C525357:SIRT4 protein, human; D037761:Sirtuins; D005947:Glucose