丝苏氨酸蛋白激酶NDR1在抗病毒天然免疫中的调控作用及其分子机制

发布时间：2018-05-16 19:17

  本文选题：STAT1 + NDR1　； 参考：《浙江大学》2016年博士论文

【摘要】：天然免疫系统是机体抵抗外来病原微生物感染的第一道防线。在病毒感染机体时,机体模式识别受体通过识别病毒中病原相关模式分子启动抗病毒天然免疫应答反应,上调Ⅰ型干扰素及炎性细胞因子。Ⅰ型干扰素与干扰素受体结合,诱导直接发挥抗病毒效应的干扰诱导基因(Interferon Stimulated Genes,ISGs)的表达,同时正向反馈干扰素产生信号通路。机体干扰素应答需要受到严格的调控,若病毒入侵过程干扰素应答过低将导致病毒持续感染,反之应答过强将导致严重组织损伤及自身免疫性疾病的发生。在本研究中,我们发现丝苏氨酸蛋白激酶NDR1(Nuclear Dbf2p-related kinase 1)正向调控抗病毒天然免疫应答。干扰或者敲除小鼠腹腔巨噬细胞中NDR1,显著抑制了病毒感染引起的Ⅰ型干扰素、炎性细胞因子及抗病毒相关的干扰素诱导基因ISGs的产生。小鼠巨噬细胞系RAW264.7中过表达NDR1及其激酶活性突变体均可促进病毒感染诱导的Ⅰ型干扰素、炎性细胞因子及抗病毒相关的干扰素诱导基因ISGs的产生,表明NDR1发挥抗病毒功能不依赖其蛋白激酶活性。VSV感染小鼠后,NDR1缺失小鼠组与野生对照组相比,其生存率明显降低,外周血中Ⅰ型干扰素及炎性细胞因子表达量下降,病毒感染导致的组织损伤更加严重。机制研究发现,NDR1促进STAT1蛋白质翻译,进而促进干扰素信号通路,发挥抗病毒功能。进一步研究发现NDR1通过抑制miRNA146a的表达,促进STAT1的翻译。NDR1可以作为转录调控因子结合于miRNA146a启动子区,通过与NF-kB相互作用,抑制miRNA146a转录,进而解除miRNA146a对STAT1的翻译抑制,最终在病毒感染机体时通过正向调控干扰素信号通路,发挥抗病毒功能。我们的研究结果首次揭示了 NDR1以激酶非依赖形式促进STAT1翻译过程,为深入了解抗病毒反应的分子机制提供新思路。此外,我们的研究发现NDR1正向调控机体抗病毒天然免疫反应的新功能,提出一种新的机体抵抗病毒感染和防止病毒免疫逃逸的新机制。
[Abstract]:The innate immune system is the first line of defense against the infection of foreign pathogenic microorganisms. When the virus infects the body, the host pattern recognition receptor initiates the antiviral innate immune response by recognizing the pathogen-associated model molecules in the virus, upregulating the type I interferon and inflammatory cytokines. Type I interferon binds to the interferon receptor. Interferon Stimulated genes were induced to express ISGs and interferon produced signal pathway. The response of interferon in organism needs to be strictly regulated. If the response of interferon is too low during virus invasion, it will lead to persistent infection of virus, otherwise, excessive response will lead to serious tissue damage and autoimmune disease. In this study, we found that Serotonine protein kinase (NDR1(Nuclear Dbf2p-related kinase 1) positively regulates the anti-viral innate immune response. By interfering with NDR1 in peritoneal macrophages of knockout mice, the production of type I interferon, inflammatory cytokines and anti-virus related interferon-induced gene ISGs was significantly inhibited. Overexpression of NDR1 and its kinase active mutants in murine macrophage RAW264.7 can promote the production of interferon type I, inflammatory cytokines and anti-virus related interferon-induced gene ISGs. The results showed that the survival rate and the expression of interferon type I and inflammatory cytokines in peripheral blood of the mice without NDR1 infection were significantly lower than those of the wild control group, and the expression of IFN- 鈪，

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