Sirtuin 4 Explained

Sirtuin 4, also known as SIRT4, is a mitochondrial protein which in humans is encoded by the SIRT4 gene.^{[1] [2]} SIRT4 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein. SIRT4 exhibits NAD+-dependent deacetylase activity.

Function

SIRT4 is a mitochondrial ADP-ribosyltransferase that inhibits mitochondrial glutamate dehydrogenase 1 activity, thereby downregulating insulin secretion in response to amino acids.^[3] A deacetylation of malonyl-CoA decarboxylase enzyme by SIRT4 represses the enzyme activity, inhibiting fatty acid oxidation in muscle and liver cells.^{[4] [5]} SIRT4 has a suppressive effect on peroxisome proliferator-activated receptor alpha (PPAR-α) which downregulates fatty acid oxidation in liver cells. Deacetylation of ADP/ATP translocase 2 (ANT2) increases cellular ATP by dampening mitochondrial uncoupling.

Clinical significance

SIRT4 is a mitochondrial tumor suppressor protein. Overexpression of SIRT4 inhibits cancer cell proliferation by inhibition of glutamine metabolism.^[6]

Further reading

• Yamamoto H, Schoonjans K, Auwerx J . Sirtuin functions in health and disease. . Mol. Endocrinol. . 21 . 8 . 1745–55 . 2007 . 17456799 . 10.1210/me.2007-0079 . free .
• Michishita E, Park JY, Burneskis JM, etal . Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins . Mol. Biol. Cell . 16 . 10 . 4623–35 . 2005 . 16079181 . 10.1091/mbc.E05-01-0033 . 1237069 .
• Reiling E, van Vliet-Ostaptchouk JV, van 't Riet E, etal . Genetic association analysis of 13 nuclear-encoded mitochondrial candidate genes with type II diabetes mellitus: the DAMAGE study. Eur. J. Hum. Genet. . 17 . 8 . 1056–62 . 2009 . 19209188 . 2986549 . 10.1038/ejhg.2009.4 .
• Gerhard DS, Wagner L, Feingold EA, etal . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–27 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• Nita Ahuja . Ahuja N, Schwer B, Carobbio S, etal . Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. . J. Biol. Chem. . 282 . 46 . 33583–92 . 2007 . 17715127 . 10.1074/jbc.M705488200 . free .
• Toward a complete human genome sequence . Genome Res. . 8 . 11 . 1097–108 . 1998 . 9847074 . 10.1101/gr.8.11.1097. Sanger Centre . The . Washington University Genome Sequencing Cente . The . free .
• Frye RA . Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. . Biochem. Biophys. Res. Commun. . 273 . 2 . 793–98 . 2000 . 10873683 . 10.1006/bbrc.2000.3000 .
• Irobi J, Van Impe K, Seeman P, etal . Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. . Nat. Genet. . 36 . 6 . 597–601 . 2004 . 15122253 . 10.1038/ng1328 . free .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–16903 . 2002 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Scherer SE, Muzny DM, Buhay CJ, etal . The finished DNA sequence of human chromosome 12 . Nature . 440 . 7082 . 346–51 . 2006 . 16541075 . 10.1038/nature04569 . 2006Natur.440..346S . free .

Notes and References

1. Frye RA . 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 . Biochem. Biophys. Res. Commun. . 260 . 1 . 273–79 . June 1999 . 10381378 . 10.1006/bbrc.1999.0897 .
2. Web site: Entrez Gene: Sirtuin 4 .
3. Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, Valenzuela DM, Yancopoulos GD, Karow M, Blander G, Wolberger C, Prolla TA, Weindruch R, Alt FW, Guarente L . SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells . Cell . 126 . 5 . 941–54 . September 2006 . 16959573 . 10.1016/j.cell.2006.06.057 . 1391160 . free .
4. Nasrin N, Wu X, Fortier E, Feng Y, Bare' OC, Chen S, Ren X, Wu Z, Streeper RS, Bordone L . SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. In primary myotubes and hepatocytes, knockdown of SIRT4 results in increased Fatty Acid Oxidation, cellular respiration, and pAMPK levels. SIRT4 inhibition increases fat oxidative capacity in liver and mitochondrial function in muscle, which might provide therapeutic benefits for diseases associated with ectopic lipid storage such as type 2 diabetes. . J. Biol. Chem. . 285 . 42 . 31995–32002 . October 2010 . 20685656 . 2952200 . 10.1074/jbc.M110.124164 . free .
5. Li S, Zheng W . Mammalian Sirtuins SIRT4 and SIRT7 . . Progress in Molecular Biology and Translational Science . 154 . 147–168 . 2018 . 10.1016/bs.pmbts.2017.11.001 . 29413176. 9780128122617 .
6. Yoo HC, Yu YC, Sung Y, Han JM. Glutamine reliance in cell metabolism . . 52 . 9 . 1496–1516 . 2020 . 10.1038/s12276-020-00504-8 . 32943735. 8080614 . free .