Role of SIRT7 in hepatic lipid metabolism

Abstract

Sirtuins are evolutionarily conserved enzymes that regulate a wide variety of biological processes, such as aging, genomic stability, tumorigenesis, and metabolism [1]. To date, seven sirtuins have been identified in mammals (SIRT1–SIRT7), which share a highly conserved NADbinding and catalytic core domain, but have distinct flanking Nand C-terminal domains. The divergent Nand C-termini of sirtuins are responsible for the different functions and subcellular localizations of these enzymes. Although sirtuins were originally described as NAD-dependent histone deacetylases, these enzymes are now known to act not only on histones, but also on numerous transcription factors and enzymes. SIRT1 controls the acetylation of proliferator-activated receptor-c co-activator 1a (PGC1a), p53, and forkhead box O, among other targets, whereas SIRT3 is a major deacetylase in mitochondria [2, 3]. In addition, a few sirtuins have either weak or undetectable deacetylase activity. For example, SIRT4 is reported to act as an ADP-ribosyltransferase [4], and SIRT5 has both demalonylase and desuccinylase activities [5]. SIRT6 has been shown to deacetylate acetylated lysine 9 of histone H3 (H3K9Ac) and was also recently reported to preferentially hydrolyze long-chain fatty acyl groups on acylated protein targets [6]. SIRT7 mRNA is ubiquitously expressed in all tissues examined to date, with the exception of skeletal muscle [7]. Human (NP_057622.1), mouse (NP_694696.2), and rat (NP_001100543.1) SIRT7 proteins consist of 400, 402, and 402 amino acids, respectively. Human SIRT7 contains a conserved NAD-binding and catalytic core domain (amino acids 90–331) as well as flanking N-terminal (amino acids 1–89) and C-terminal (332–400) regions (Fig. 1a). The histidine residue at position 187 (H187) (corresponding to mouse H188) is highly conserved among sirtuins and is reported to be important for binding with NAD [8]. The N-terminal region of SIRT7 contains a nuclear localization signal (NLS) (LQGRSRRREGLKRRQE, amino acids 61–76), and the C-terminal region contains a nucleolar localization signal (NoLS) (KRTKRKKVT, amino acids 392–400) [9]. SIRT7 is enriched in the nucleolus, but is also present in the nucleoplasm (Fig. 1b). In contrast to SIRT1 to SIRT6, the enzymatic activity and physiological functions of SIRT7 were poorly defined until recently. SIRT7 was first reported to promote ribosomal RNA transcription by interacting with RNA polymerase I (Pol I) and the transcription factor UBF [7, 10]. PAF53, a subunit of Pol I that is required for rDNA transcription, was recently identified as a target of SIRT7 [11]. SIRT7 was also shown to function as NAD-dependent deacetylase with high selectivity for acetylated lysine 18 of histone H3 (H3K18Ac) [12]. This deacetylase activity plays a role in the gene-specific transcriptional repression of a select subset of H3K18Ac-containing promoters, such as RPS20 and NME1 [12]. H3K18Ac-specific deacetylation by SIRT7 is important for maintaining the phenotype and stabilizing the tumorigenicity of human cancer cells [12]. Our group also demonstrated that Myb-binding protein 1a (Mybbp1a) binds to SIRT7, thereby inhibiting the deacetylation of H3K18 [13]. & Kazuya Yamagata k-yamaga@kumamoto-u.ac.jp