去乙酰化酶Sirt1对细胞程序性坏死的调控机制

发布时间：2018-11-14 20:37

【摘要】：凋亡诱导因子(apoptosis inducing factor,AIF)是一种存在于线粒体膜间隙中的保守的黄素蛋白,广泛存在于多种组织和细胞中。它具有FAD依赖性的NADH氧化还原酶活性,在正常情况下AIF定位在线粒体内参与线粒体的氧化还原反应、维持线粒体结构。但是在凋亡信号刺激下AIF被钙调蛋白酶或组织蛋白酶切割形成一种可溶性蛋白,从线粒体中释放进入细胞质再穿梭入核,在细胞核中与CypA和rH2AX结合,以一种不依赖于caspase的方式在细胞核内引起染色体的凝集和DNA的大片段化(50kbp),最终导致细胞凋亡。AIF诱导的细胞凋亡为我们进一步了解凋亡的发生机制提供了新的靶点。Sirtl是一种NAD(烟酰胺腺嘌呤二核苷酸)依赖性的去乙酰化酶,可以去乙酰化组蛋白和非组蛋白,属于第三类组蛋白去乙酰化酶(HDACs),与Sir2(酵母沉默信息调节因子2)具有同源性较高,在哺乳动物细胞中广泛存在。Sirtl能够与多种蛋白因子相互作用,参与多种细胞生理功能的调节过程,比如细胞衰老、凋亡、神经保护、糖脂类代谢、炎症氧化应激等。在本课题研究中,我们发现了Sirt1的一种新的结合蛋白。研究发现该蛋白是AIF,且在信号凋亡刺激下AIF与Sirtl的结合增强,内源性的AIF和Sirtl也会发生共定位现象。细胞发生凋亡时,AIF的乙酰化水平升高,但是当外源Sirtl过量表达时,Sirt1能够对AIF发挥其去乙酰化功能。Sirt1还能够干扰AIF与CypA的结合及AIF介导的DNA大片段化过程。
[Abstract]:Apoptosis-inducing factor (apoptosis inducing factor,AIF) is a conserved flavin protein in mitochondrial membrane space, which is widely found in many tissues and cells. It has FAD dependent NADH redox enzyme activity. Under normal conditions, AIF participates in mitochondrial redox reaction and maintains mitochondrial structure. However, stimulated by apoptotic signals, AIF was cut by calmodulin or cathepsin to form a soluble protein, which was released from the mitochondria into the cytoplasm and then shuttled into the nucleus to bind to CypA and rH2AX in the nucleus. In a way that does not depend on caspase, it causes the agglutination of chromosomes and the large fragmentation of DNA (50kbp) in the nucleus. The apoptosis induced by AIF provides a new target for further understanding the mechanism of apoptosis. Sirtl is a NAD (nicotinamide adenine dinucleotide)-dependent deacetylase. Histone and non-histone can be deacetylated. The homology of histone deacetylase (HDACs), and Sir2 (yeast silencing information regulatory factor 2) is high. Sirtl can interact with many protein factors and participate in the regulation of many cell physiological functions, such as cell senescence, apoptosis, neuroprotection, glucose and lipid metabolism, inflammatory oxidative stress and so on. In this study, we found a new binding protein of Sirt1. It was found that the protein was AIF, and the binding of AIF to Sirtl was enhanced under the stimulation of signal apoptosis. The co-localization of endogenous AIF and Sirtl was also observed. During apoptosis, the acetylation level of AIF increased, but when exogenous Sirtl was overexpressed, Sirt1 could play its role in deacetylation of AIF. Sirt1 could also interfere with the combination of AIF and CypA and AIF mediated DNA fragmentation.
【学位授予单位】：华东师范大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R329.2

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