本文選題：STAT1 + NDR1　； 參考：《浙江大學(xué)》2016年博士論文

【摘要】：天然免疫系統(tǒng)是機(jī)體抵抗外來病原微生物感染的第一道防線。在病毒感染機(jī)體時(shí),機(jī)體模式識(shí)別受體通過識(shí)別病毒中病原相關(guān)模式分子啟動(dòng)抗病毒天然免疫應(yīng)答反應(yīng),上調(diào)Ⅰ型干擾素及炎性細(xì)胞因子。Ⅰ型干擾素與干擾素受體結(jié)合,誘導(dǎo)直接發(fā)揮抗病毒效應(yīng)的干擾誘導(dǎo)基因(Interferon Stimulated Genes,ISGs)的表達(dá),同時(shí)正向反饋干擾素產(chǎn)生信號通路。機(jī)體干擾素應(yīng)答需要受到嚴(yán)格的調(diào)控,若病毒入侵過程干擾素應(yīng)答過低將導(dǎo)致病毒持續(xù)感染,反之應(yīng)答過強(qiáng)將導(dǎo)致嚴(yán)重組織損傷及自身免疫性疾病的發(fā)生。在本研究中,我們發(fā)現(xiàn)絲蘇氨酸蛋白激酶NDR1(Nuclear Dbf2p-related kinase 1)正向調(diào)控抗病毒天然免疫應(yīng)答。干擾或者敲除小鼠腹腔巨噬細(xì)胞中NDR1,顯著抑制了病毒感染引起的Ⅰ型干擾素、炎性細(xì)胞因子及抗病毒相關(guān)的干擾素誘導(dǎo)基因ISGs的產(chǎn)生。小鼠巨噬細(xì)胞系RAW264.7中過表達(dá)NDR1及其激酶活性突變體均可促進(jìn)病毒感染誘導(dǎo)的Ⅰ型干擾素、炎性細(xì)胞因子及抗病毒相關(guān)的干擾素誘導(dǎo)基因ISGs的產(chǎn)生,表明NDR1發(fā)揮抗病毒功能不依賴其蛋白激酶活性。VSV感染小鼠后,NDR1缺失小鼠組與野生對照組相比,其生存率明顯降低,外周血中Ⅰ型干擾素及炎性細(xì)胞因子表達(dá)量下降,病毒感染導(dǎo)致的組織損傷更加嚴(yán)重。機(jī)制研究發(fā)現(xiàn),NDR1促進(jìn)STAT1蛋白質(zhì)翻譯,進(jìn)而促進(jìn)干擾素信號通路,發(fā)揮抗病毒功能。進(jìn)一步研究發(fā)現(xiàn)NDR1通過抑制miRNA146a的表達(dá),促進(jìn)STAT1的翻譯。NDR1可以作為轉(zhuǎn)錄調(diào)控因子結(jié)合于miRNA146a啟動(dòng)子區(qū),通過與NF-kB相互作用,抑制miRNA146a轉(zhuǎn)錄,進(jìn)而解除miRNA146a對STAT1的翻譯抑制,最終在病毒感染機(jī)體時(shí)通過正向調(diào)控干擾素信號通路,發(fā)揮抗病毒功能。我們的研究結(jié)果首次揭示了 NDR1以激酶非依賴形式促進(jìn)STAT1翻譯過程,為深入了解抗病毒反應(yīng)的分子機(jī)制提供新思路。此外,我們的研究發(fā)現(xiàn)NDR1正向調(diào)控機(jī)體抗病毒天然免疫反應(yīng)的新功能,提出一種新的機(jī)體抵抗病毒感染和防止病毒免疫逃逸的新機(jī)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，

本文編號：1898089