摘要
目的：研究Ⅲ类组蛋白去乙酰化酶Sirtl对转录因子AP-1(activator protein-1)的转录抑制作用,及Sirtl通过AP-1抑制COX-2 (cyclooxygenase-2)的表达,下调巨噬细胞炎症反应,改善巨噬细胞的功能及其机制。
背景：Sirt1是酵母染色质沉默因子(Silent information regulator 2, Sir2)的哺乳动物同源体,属于Ⅲ类组蛋白去乙酰化酶。Ⅲ类组蛋白去乙酰化酶参与的反应依赖于烟酰胺腺嘌呤二核苷酸(nicotinamid adenine dinecleotide, NAD+),这不同于Ⅰ类和Ⅱ类组蛋白去乙酰化酶。Sir2家族的蛋白从细菌到人类都具有高度保守性,人Sirtuins是与Sir2具有同源性的一个家族,其中Sirt1是与Sir2同源性最高的一个成员,在许多生命过程,如细胞凋亡、细胞周期、DNA损伤修复、重组、长寿和基因沉默中都发挥了重要的作用。近年来的研究表明,Sirt1不仅可以去乙酰化组蛋白如组蛋白H3、H4等,而且与很多转录因子和转录辅因子相互作用,调节它们的转录激活作用。这些转录因子包括：p53、FOXO家族、NF-KB(p65)、MyoD等；转录辅因子包括：NcoR、p300、PGC-1α等。
转录因子AP-1是由结构功能相关的亚家族亚单位组成的二聚体。这些成员均有进化保守的亮氨酸拉链(leucine zipper)又称碱性拉链(bZIP)结构域。c-Fos和c-Jun是哺乳动物细胞内最为常见的两种AP-1亚单位。AP-1对细胞因子、生长因子、感染及致癌刺激等生理或病理信号发生应答,通过bZIP结构域的碱性区域与DNA序列结合,调节基因的转录,参与细胞的增殖、分化等过程。AP-1的活性调节是通过多方面来完成的,包括转录调节、翻译后修饰、AP-1分子的二聚化及和其他辅助蛋白的相互作用调节。COX-2是研究最为深入的AP-1下游分子之一,在巨噬细胞中,COX-2的活性参与炎症反应和巨噬细胞功能调节。
材料和方法：本实验首先在HEK293细胞中通过荧光素酶报告基因实验方法检测了Sirt1在基础水平和PMA处理下对AP-1的转录活性的影响。随后通过免疫共沉淀的方法确定了Sirt1和c-Fos、c-Jun相互作用的具体结构域。应用EMSA的方法,检测了Sirt1对AP-1的DNA结合活性的影响。通过荧光素酶报告基因实验ChIP、Western blotting及PGE2测定等检测Sirt1对AP-1下游基因COX-2表达及功能的影响。用K562和Jurkat细胞作为目标细胞,检测巨噬细胞的肿瘤杀伤活性；用FITC标记酵母作为吞噬物来检测Sirt1对巨噬细胞吞噬功能的影响。随后制备能量限制小鼠模型,模拟Sirt1高表达状态,检测巨噬细胞COX-2的表达、活性及巨噬细胞功能。结果：本研究发现Sirt1可以抑制基础水平和PMA诱导的AP-1的转录激活作用。AP-1家族中最广泛表达的c-Fos, c-Jun可以和Sirt1相互作用。进一步研究确定了c-Fos、c-Jun碱性DNA结合区参与介导了与Sirt1的相互作用。Sirt1抑制了c-Fos、c-Jun的乙酰化水平,并且抑制了AP-1的DNA结合能力。实验表明Sirt1抑制了AP-1的下游基因COX-2启动子活性。在巨噬细胞中,腺病毒介导的Sirt1高表达下调的COX-2的蛋白水平和COX-2的产物PGE2的生成。进一步的功能学实验表明,Sirt1对巨噬细胞的肿瘤杀伤能力和吞噬能力具有增强和保护作用,这可能是通过抑制COX-2活性来实现的。能量限制小鼠腹腔巨噬细胞Sirt1表达上调。与同窝正常饮食小鼠相比,能量限制小鼠巨噬细胞COX-2表达降低,肿瘤杀伤和吞噬功能增强,模拟了Sirt1过表达的实验效果,从另一方面证明Sirt1的作用。进一步研究发现PMA可以诱导巨噬细胞内Sirt1的表达,这可能是一种细胞的负反馈保护机制,从而防止细胞在某些刺激作用下炎症反应过于激烈,对细胞造成不可逆的损伤,从而保护细胞功能状态。
结论：我们首次发现AP-1可能是Sirt1的一个新的底物分子。Sirt1可以通过和c-Fos、c-Jun结合并降低c-Fos、c-Jun乙酰化水平,抑制AP-1与DNA的结合,从而进一步抑制其转录激活。在巨噬细胞内,Sirt1可能通过抑制AP-1降低了COX-2的表达及活性,从而抑制了炎症反应,保护了巨噬细胞的肿瘤杀伤和吞噬能力。因此,提高Sirt1的表达和活性可以作为一个调节炎症及免疫反应,保护机体的新的手段。
Target-To elucidate the transcriptional repression function of the histone deacetylase Sirtl on AP-1, and the effects of Sirtl on macrophage COX-2 expression and macrophage inflammatory response and functions.
Background-The silent information regulator 2 (Sir2) protein family (sirtuins or SIRTs) belongs to classⅢhistone/protein deacetylases (HDACs). Unlike the other classⅠandⅡHDACs, which require zinc for deacetylation, Sirtuins require nicotinamide adenosine dinucleotide (NAD+) as a cofactor. Sirtl, the mammalian homolog of Sir2 also mediate a variety of physiological processes such as life span, fat mobilization. Sirtl has been reported to deacetylate a broad array of targets including histones (H3, H4), transcription factors (p53, FOXO, NFκB) and transcriptional integrators (p300, NcoR, PGC-1α). AP-1, a transcriptional factor composed of homodimers or heterodimers of Jun, Fos, Maf and ATF families, is known to be proto-oncogenes. In response to growth factors, cytokines, oxidative stress and PMA, AP-1 could bind to the various promoters and alter the expression of genes, which are involved in cell proliferation, inflammation and so on. The c-Jun and c-Fos are the major component of cellular AP-1. The activity of AP-1 is regulated at many levels: the transcription of c-Fos and c-Jun genes, the post-translational modification of Fos and Jun proteins. Among AP-1 modifications, phosphorylation has been the most extensively studied. Sumoylation of c-Fos and c-Jun has been shown as another covalent modification of AP-1, which may down-regulate AP-1 transcriptional activity. In addition, p300-mediated acetylation of AP-1 has been reported recently. As for all bZIP transcription factors, AP-1 activity is also regulated by the composition of dimerization that is required for binding to DNA. The leucine zipper domain of c-Fos/c-Jun is required for dimerization and the basic region functions to bind to DNA. Cyclooxygenase-2(COX-2), the rate-limiting enzyme for Prostaglandins (PGs) production, has been one of the most intensively studied AP-1 target gene.
Methods-To examine the ability of Sirtl to repress AP-1 transcriptional activity, we tranniently transfected HEK293 cells with AP-1 luciferase plasmid and pcDNA3.1 or pcDNA3.1 Sirtl. Using immunoprecipitation, we identified the domain of c-Fos, c-Jun that mediated the association between AP-1 and Sirtl. We detect the AP-1 DNA binding activity by EMSA. Using luciferase assay, ChIP, western blotting and PGE2 measurement, we examined the effect of Sirtl on COX-2, one of classic AP-1 target genes. We further detected the effects of Sirtl on macrophage function including phagocytosis and tumoricidal function. Using calorie restriction moedel to mimic the overexpression of Sirtl in mice, we detect the effects of calorie restriction on macrophage COX-2 expression and macrophage function.
Results-We show here that Sirtl depresses the transcriptional activity of activator protein-1(AP-1) and directly interacts with basic DNA-binding region of c-Fos and c-Jun, which are the major components of AP-1 in most cells. c-Fos and c-Jun can be acetylated by p300 and the acetylation is reduced by the overexpression of Sirtl. Unexpectedly, the dominant-negative mutant Sirtl HY could also bind to c-Fos and c-Jun and suppress AP-1 transcriptional activity. Sirtl reduces COX-2, a typical AP-1 target gene, and improves the phagocytosis and tumoricidal function of peritoneal macrophages (MΦ). Calorie restriction (CR) could mimic the effects of Sirtl overexpression in MΦ.
Conclusion-To our knowledge, this report demonstrates for the first time that Sirtl could interact with and deacetylate AP-1 to regulate its transcriptional activity. The results of this study may provide additional insight into the mechanism underlying the effects of CR and Sirt1. We hypothesize that PMA induce COX-2 expression by AP-1 and meantime PMA still increase the Sirt1, which could counteractive the AP-1 transcriptional activity and abrogate COX-2 transcriptional expression as a feedback mechanism.
引文
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