Functions of mammalian SIRT4 in cellular metabolism and research progress in human cancer

Abstract

Sirtuins are mammalian homologs of yeast silent information regulator two (SIRT) and are a highly conserved family of proteins, which act as nicotinamide adenine dinucleotide (NAD⁺)-dependent histone deacetylases. The seven sirtuins (SIRT1-7) share a conserved catalytic core domain; however, they have different enzyme activities, biological functions, and subcellular localizations. Among them, mitochondrial SIRT4 possesses ADP-ribosyltransferase, NAD⁺-dependent deacetylase, lipoamidase, and long-chain deacylase activities and can modulate the function of substrate proteins via ADP-ribosylation, delipoylation, deacetylation and long-chain deacylation. SIRT4 has been shown to play a crucial role in insulin secretion, fatty acid oxidation, amino acid metabolism, ATP homeostasis, apoptosis, neurodegeneration, and cardiovascular diseases. In addition, recent studies have demonstrated that SIRT4 acts as a tumor suppressor. Here, the present review summarizes the enzymatic activities and biological functions of SIRT4, as well as its roles in cellular metabolism and human cancer, which are described in the current literature.

Keywords: SIRT4; cancer; cellular metabolism; enzyme activities; molecular structure.

Figure 1.

The functions of mitochondrial SIRT4 in cellular metabolism. The ADP-ribosylation on GDH and interactions with IDE and ANT2/3 can regulate insulin secretion in pancreatic β cells. The long-chain deacylation on MCCC can regulate leucine catabolism and affect insulin secretion indirectly. The delipoylation on the E2 component of the PDH complex further impacts cellular energy metabolism. The NAD+-dependent deacetylation on MCD and MTPα can inhibit fatty acid β-oxidation. In addition, SIRT4 also modulates some proteins associated with lipid metabolism (CTP1, PPARα and ECHA) and finally represses lipid catabolism collectively. GDH, glutamate dehydrogenase; IDE, insulin degrading enzyme; ANT2/3, ADP/ATP translocase 2/3; MCCC, methylcrotonyl-CoA carboxylase; PDH, pyruvate dehydrogenase; MCD, malonyl CoA decarboxylase; MTPα, mitochondrial trifunctional protein α; MGc, 3-methylglutaconyl; MG, 3-methylglutaryl; HMG, 3-hydroxy-3-methylglutaryl.