本文選題：抗病毒免疫 + E3泛素連接酶�。� 參考：《浙江大學(xué)》2015年博士論文

【摘要】：天然免疫細(xì)胞通過模式識(shí)別受體(pattern recognition receptors,PRRS)識(shí)別病原微生物相關(guān)模式啟動(dòng)天然免疫反應(yīng)抵抗病原微生物的入侵。其中維甲酸誘導(dǎo)基因Ⅰ樣受體(Retinoic acid-inducible gene I like receptor,RLRs)通過識(shí)別病毒 RNA,傳遞下游信號(hào)通路,活化了轉(zhuǎn)錄因子IRF3/7,NF-κB,AP-1,導(dǎo)致f型干擾素和炎癥因子的表達(dá)。I型干擾素能夠與細(xì)胞膜上的干擾素受體(interferon receptor,IFNR)結(jié)合,活化了細(xì)胞內(nèi)信號(hào)通路,誘導(dǎo)表達(dá)具有抑制病毒復(fù)制和感染功能的干擾素刺激基因(interferonstimulationgene,ISG)。因此I型干擾素,在抗病毒天然免疫反應(yīng)中具有非常重要的作用。蛋白質(zhì)的泛素化在天然免疫細(xì)胞識(shí)別,清除病原體和細(xì)胞信號(hào)傳導(dǎo)中發(fā)揮著非常關(guān)鍵的作用。而在蛋白質(zhì)發(fā)生泛素化過程中,E3泛素連接酶負(fù)責(zé)特異性識(shí)別靶蛋白,并將不同的泛素鏈連接到靶蛋白上,發(fā)揮著不同的功能。E3泛素連接酶FBXW7在腫瘤的發(fā)生發(fā)展,脂類代謝,細(xì)胞增殖和分化,維持干細(xì)胞的穩(wěn)態(tài)發(fā)揮著重要的作用,然而FBXW7在病毒天然免疫反應(yīng)中的作用幾乎不清楚。我們研究發(fā)現(xiàn),髓系細(xì)胞中特異性敲除FBXW7基因的小鼠(Lysm+FBXW7f/f mice)對(duì)水皰性口炎病毒(Vesicular Stomatitis Virus,VSV)感染更加敏感,VSV病毒復(fù)制更加活躍。敲除FBXW7的巨噬細(xì)胞和樹突狀細(xì)胞在VSV感染下,VSV-G mRNA明顯升高。我們發(fā)現(xiàn)這一現(xiàn)象與I型干擾素的產(chǎn)生的差異相關(guān)。敲除FBXW7的巨噬細(xì)胞和樹突狀細(xì)胞在VSV和H1N1感染下顯著減少了 I型干擾素的產(chǎn)生,III而過表達(dá)FBXW7,能夠顯著地促進(jìn)I型干擾素的產(chǎn)生。進(jìn)一步的研究發(fā)現(xiàn)FBXW7能夠促進(jìn)轉(zhuǎn)錄因子IRF3的活化,進(jìn)而增強(qiáng)了Ⅰ型干擾素的產(chǎn)生。其作用機(jī)制是FBXW7在病毒感染作用下,能夠與SHP2結(jié)合。而SHP2是RIG-I信號(hào)通路中關(guān)鍵的負(fù)向調(diào)控分子,能夠顯著抑制Ⅰ型干擾素的產(chǎn)生。FBXW7通過識(shí)別SHP2的降解子序列,催化SHP2的91位點(diǎn)的賴氨酸(91K)發(fā)生K48連接的泛素化,使SHP2通過蛋白酶體途徑發(fā)生降解,促進(jìn)Ⅰ型干擾素的產(chǎn)生。本研究揭示了 FBXW7在抗病毒天然免疫中發(fā)揮著重要的調(diào)控功能,可為深入認(rèn)識(shí)天然免疫的調(diào)節(jié)機(jī)制提供新的觀點(diǎn)并可能為治療感染性疾病提供新的思路和理論依據(jù)。
[Abstract]:Innate immune cells recognize pathogenic microorganisms by pattern recognition receptor (pattern recognition receptor / PRRS) and initiate innate immune response to the invasion of pathogenic microorganisms. Retinoic acid-inducible gene I like receptor (RLRs) transduces downstream signaling pathways by recognizing viral RNAs. Activation of transcription factor IRF3 / 7 NF- 魏 BmAP-1resulted in the expression of interferon type f and inflammatory factor I, which could bind to the interferon receptor (IFNR) on the cell membrane and activate the intracellular signaling pathway. Interferon stimulating ISG (ISG) was induced to express interferon stimulating gene (ISG) which can inhibit viral replication and infection. Therefore, interferon I plays a very important role in anti-viral innate immune response. Protein ubiquitin plays a key role in innate immune cell recognition, pathogen clearance and cell signal transduction. In the process of protein ubiquitin ligation, E3 ubiquitin ligase is responsible for the specific recognition of target proteins, and links different ubiquitin chains to target proteins, which play different functions. E3 ubiquitin ligase FBXW7 plays a different role in tumorigenesis and development and lipid metabolism. Cell proliferation and differentiation and maintenance of stem cell homeostasis play an important role, but the role of FBXW7 in the innate immune response of virus is almost unknown. We found that Lysm FBXW7fr / f mice was more sensitive to vesicular stomatitis virus infection than Lysm FBXW7 gene knockout mice (Lysm FBXW7f / f mice). Macrophages and dendritic cells knockout FBXW7 were significantly increased in VSV-G mRNA under VSV infection. We found that this phenomenon was related to the difference in the production of type I interferon. The knockout macrophages and dendritic cells of FBXW7 significantly reduced the production of interferon type I and overexpression of FBXW7 under VSV and H1N1 infection, which could significantly promote the production of interferon type I. Further studies have shown that FBXW7 can promote the activation of transcription factor IRF3 and further enhance the production of interferon type I. The mechanism is that FBXW7 can bind to SHP2 in the presence of virus infection. SHP2 is a key negative regulatory molecule in the RIG-I signaling pathway, which can significantly inhibit the production of interferon type I. FBXW7 catalyzes the K48-linked ubiquialization of lysine (91K) at the 91 site of SHP2 by recognizing the degradation subsequence of SHP2. SHP2 was degraded by proteasome pathway and the production of interferon type I was promoted. This study revealed that FBXW7 plays an important regulatory role in antiviral innate immunity, which can provide a new viewpoint for further understanding the regulatory mechanism of innate immunity and may provide new ideas and theoretical basis for the treatment of infectious diseases.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R392

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