SIRT1调控其下游非组蛋白分子乙酰化修饰影响细胞凋亡的分子机制

The Molecular Mechanism of SIRT1-Catalysed Deacetylation on Non-Histone Proteins and Its Impact on Cell Apoptosis

Sirtuin家族是酵母沉默信息调节因子(silent information regulator factor)在哺乳动物中的同源物,属于Ⅲ类组蛋白去乙酰化酶。沉默信息调节因子2相关酶1(silent information regulator factor 2-related enzyme 1,SIRT1)是Sirtuin家族目前研究最为充分的成员之一。主要分布于细胞核及细胞质,通过行使其NAD+依赖的去乙酰化活性,参与调节DNA损伤修复、基因转录、能量代谢、应激及凋亡等细胞生理过程。细胞凋亡是在精确的内在遗传调控下发生的一种程序性死亡,旨在维持机体内环境稳态。异常的细胞凋亡参与多种疾病的发生,例如肿瘤、神经退行性病变、自身免疫病和缺血性疾病等,了解细胞凋亡的机制对于这些疾病的治疗有着极为重要的意义。SIRT1除靶向组蛋白外,还作用于多种非组蛋白质例如转录因子和蛋白激酶等,其中有很多非组蛋白分子都与细胞凋亡息息相关。本文总结了SIRT1通过调控相关下游非组蛋白分子p53、叉头转录因子FOXO3a、AMP依赖的蛋白激酶(AMPK)、核转录因子NF-κB、ku70蛋白、转录因子E2F1和缺氧诱导因子-1α的乙酰化修饰水平,进而影响基因转录、DNA损伤修复、炎症、氧化应激等过程,直接或间接触发细胞凋亡的分子机制。希望通过调控SIRT1表达来影响其下游非组蛋白分子的乙酰化修饰水平,进而对细胞凋亡进行干预,为多种相关疾病的治疗提供新的靶点。

Sirtuins belongs to the class Ⅲ family of histone deacetylases(HDAC), which is a mammalian homolog of the yeast silencing information regulator Sir2. Silent information regulator factor 2-related enzyme 1(SIRT1) is the most well studied family member of Sirtuins. Distributed mainly in the nucleus and cytoplasm, SIRT1 is involved in various intracellular biological processes, including DNA damage repair, gene transcription, energy metabolism, stress and apoptosis through its NAD+-dependent deacetylation activity. Apoptosis is a kind of programmed death that occurs under the regulation of precise intrinsic genetic program, which aims to maintain the homeostasis of the environment. Abnormal cell apoptosis results in multiple diseases such as tumors, neurodegenerative diseases, autoimmune diseases and ischemic diseases, rendering the mechanism of cell apoptosis unprecedentedly significant for the treatment of these diseases. SIRT1 deacetylates a broad range of transcription factors, such as histone proteins, protein kinases, and so on. A variety of non-histone molecules downstream of SIRT1 are closely related to cell apoptosis. In the current review, we summarized recent advances illustrating SIRT1 mediated acetylation of related non-histone downstream effectors, such as p53, forkhead transcription factor FOXO3 a, AMP-dependent protein kinase(AMPK), nuclear transcription factor NF-κB, ku70 protein, transcription factor E2 F1 and hypoxia inducible factor-1α. Furthermore, we also reviewed the roles of SIRT1 mediated acetylation in the processes of gene transcription, DNA damage repair, inflammation or oxidative stress, which directly or indirectly trigger cell apoptosis. These studies make it possible to alter the acetylation level of transcription factors and enzymes above, thus interfering cell apoptosis ultimately through regulating the expression of SIRT1, which may provide a new potential target of treatment for relevant diseases.