Role of SIRT7 in hepatic lipid metabolism
Role of SIRT7 in hepatic lipid metabolism
复制标题
SIRT7在肝脏脂质代谢中的作用
DOI：
10.1007/s13340-015-0226-y
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发表时间：
2015
影响因子：
2.2
通讯作者：
Yamagata K.
中科院分区：
文献类型：
--
作者：
Kawahara;Y;Yamagata K.
沉默调节蛋白是进化上保守的酶，其调节多种生物过程，例如衰老、基因组稳定性、肿瘤发生和代谢[1]。到目前为止，已经在哺乳动物中鉴定了七种sirtuins（SIRT 1-SIRT 7），它们共享高度保守的NAD+结合和催化核心结构域，但具有不同的侧翼N-和C-末端结构域。不同的N-和C-末端的sirtuins负责不同的功能和亚细胞定位的这些酶。虽然sirtuins最初被描述为NAD+依赖性组蛋白脱乙酰酶，但现在已知这些酶不仅作用于组蛋白，而且作用于许多转录因子和酶。SIRT 1控制增殖物激活受体-c辅激活因子1a（PGC 1a）、p53和叉头盒O等靶标的乙酰化，而SIRT 3是线粒体中的主要脱乙酰酶[2，3]。此外，少数sirtuins具有弱或不可检测的脱乙酰酶活性。例如，据报道SIRT 4充当ADP-核糖基转移酶[4]，而SIRT 5具有脱丙二酸酶和脱琥珀酸酶活性[5]。已显示SIRT 6使组蛋白H3的乙酰化赖氨酸9（H3 K9 Ac）脱乙酰化，并且最近还报道优先水解酰化蛋白质靶标上的长链脂肪酰基[6] AIRT 7 mRNA在迄今为止检查的所有组织中普遍表达，骨骼肌除外[7]。人（NP_057622. 1）、小鼠（NP_694696. 2）和大鼠（NP_001100543. 1)SIRT 7蛋白分别由400、402和402个氨基酸组成。人SIRT 7含有保守的NAD+结合和催化核心结构域（氨基酸90-331）以及侧翼N-末端（氨基酸1-89）和C-末端（332-400）区域（图1a）。第187位（H187）（对应于小鼠H188）的组氨酸残基在沉默调节蛋白中高度保守，据报道对于与NAD+结合很重要[8]。SIRT 7的N端区域含有核定位信号（NLS）（LQGRSRRREGLKRRQE，氨基酸61-76），C端区域含有核仁定位信号（NoLS）（KRTKRKKVT，氨基酸392-400）[9]。SIRT 7在核仁中富集，但也存在于核质中（图1 B）。与SIRT 1至SIRT 6相比，SIRT 7的酶活性和生理功能直到最近才被很好地定义。SIRT 7首次被报道通过与RNA聚合酶I（Pol I）和转录因子UBF相互作用来促进核糖体RNA转录[7，10]。PAF 53是rDNA转录所需的Pol I亚基，最近被鉴定为SIRT 7的靶标[11]。SIRT 7还显示出作为NAD+依赖性脱乙酰酶的功能，对组蛋白H3的乙酰化赖氨酸18（H3 K18 Ac）具有高选择性[12]。这种脱乙酰酶活性在含H3 K18 Ac启动子的选择子集（例如RPS 20和NME 1）的基因特异性转录抑制中起作用[12]。通过SIRT 7的H3 K18 Ac特异性脱乙酰化对于维持人癌细胞的表型和稳定致瘤性是重要的[12]。我们的研究小组还证明了Myb结合蛋白1a（Mybbp 1a）与SIRT 7结合，从而抑制H3 K18的脱乙酰化[13]。
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 NAD+-binding and catalytic core domain, but have distinct flanking N-and C-terminal domains. The divergent N-and 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. 1 a). 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. 1 b). 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].