需要NAD依赖性去乙酶SIRT2来进行编程性亡
Nisha Narayan1, In Hye Lee, Ronen Borenstein
1Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland 20892, USA.
Nature
|December 4, 2012
概括
通过脱乙RIP1,SIRT2通过防止RIP1-RIP3复合物的形成来调节编程性亡. 抑制SIRT2可以防止诸如缺血-再输血等损伤,这表明瘤的治疗潜力.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 生物化学 生物化学
背景情况:
- 细胞亡,曾经被认为是不受管制的,现在被理解为遵循特定的分子路径.
- 瘤坏死因子-α (TNF-α) 通过形成受体相互作用蛋白1 (RIP1) 和受体相互作用蛋白3 (RIP3) 复合体来触发坏死.
- 这种RIP1-RIP3复合体形成的调节仍然在很大程度上是未知的.
研究的目的:
- 调查SIRT2在调节计划性亡中的作用.
- 为了确定SIRT2是否调节RIP1-RIP3复合体的形成.
- 评估SIRT2抑制在涉及死的疾病中的治疗潜力.
主要方法:
- 评估了SIRT2与RIP3的构成性结合.
- 在小鼠中进行SIRT2删除或淘汰,以评估其对RIP1-RIP3复合体形成的影响.
- 在存在遗传或药理学SIRT2抑制的情况下测量了TNF-α诱导的亡.
- 分析了RIP1脱乙烯化及其对RIP1-RIP3复合体形成和亡的影响,使用功能增益和丧失突变物.
- 使用缺血-再输液损伤模型来评估SIRT2.2在体内作用.
主要成果:
- SIRT2 构成性地与 RIP3 结合,而它的缺失可以防止 RIP1-RIP3 复合体的形成.
- 抑制SIRT2阻断TNF-α诱导的细胞死亡.
- RIP1是SIRT2-依赖脱乙烯化的关键标,通过RIP1 lysine 530的乙烯化调节复合体形成和亡.
- 在体内,SIRT2抑制可以防止缺血症-再输液损伤.
结论:
- SIRT2是编程性亡的关键调节者.
- 用抑制剂向SIRT2可能为死亡损伤提供一种新的治疗策略,包括缺血性中风和心肌梗塞.
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