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標題: | STAT3與PLSCR2 協同作用去負調節第一型干擾素的反應 STAT3 cooperates with PLSCR2 to suppress type I interferon response |
作者: | Ming-Hsun Tsai 蔡明勳 |
指導教授: | 李建國(Chien-Kuo Lee) |
關鍵字: | STAT3,PLSCR2,第一型干擾素,干擾素下游基因,棕櫚酸酯化, STAT3,PLSCR2,type I interferon,interferon-stimulated gene,palmitoylation, |
出版年 : | 2018 |
學位: | 博士 |
摘要: | 第一型干擾素(IFN-I)是一種具有多功效的細胞激素去調節先天及適應性免疫反應。我們在先前已發現STAT3可藉其蛋白質N端去抑制第一型干擾素反應,這個作用和DNA結合能力及轉錄功能無關,我們利用酵母菌雜交法去發現PLSCR2可結合STAT3去抑制第一型干擾素的反應。PLSCR2是一個干擾素下游基因(IFN-stimulated gene) 且主要在細胞核中類似核小體的結構與STAT3結合,而大量表現PLSCR2會減弱ISRE報導基因的活性,如果STAT3和PLSCR2的一起表現會使這個現象更明顯。此外,PLSCR2的缺失會增強第一型干擾素下游基因的表現以及抗病毒活性,這個作用不是去影響STAT1和STAT2的活化及進核以及ISGF3的組合,而是藉由抑制ISGF3和啟動子結合來達成,此外,STAT3的存在會加強這個抑制的效果。另外我們也發現這抑制效果與STAT3的結合能力以及PLSCR2的棕櫚酸酯化(palmitoylation)有關。PLSCR2也可以和STAT2結合而調節ISGF3的轉錄活性,但STAT2的抑制機轉和PLSCR2棕櫚酸酯化無關,可見得STAT2跟與STAT3的作用不一樣。最後,我們產生PLSCR2基因剔除小鼠並測試其抗病毒感染的能力。PLSCR2缺陷的小鼠在腳墊注射口炎病毒(VSV)後比正常控制組的小鼠較不容易死亡。然而如果是用流感病毒(IAV)做鼻腔感染,則相反比較容易死亡,其原因可能是因為過度發炎反應所導致。的確,PLSCR2缺陷小鼠在脂多醣(LPS)所引發的全身性休克測試中也呈現出比較容易死亡的症狀,這些結果顯示PLSCR2的確在體內實驗中也具有抑制抗病毒反應及抗發炎作用。總合來看,我們的研究提出了一個新穎的STAT3-PLSCR2軸去微調第一型干擾素的反應。 Type I interferon (IFN-I) is a pluripotent cytokine that modulates innate and adaptive immunity. We have previously shown that STAT3 suppresses IFN-I response in a manner dependent on its N-terminal domain (NTD), but independent of its DNA-binding and transactivation ability. Using the yeast two-hybrid system, we have identified phospholipid scramblase 2 (PLSCR2) as a STAT3 NTD binding partner and a suppressor of IFN-I response. PLSCR2 is an IFN-stimulated gene (ISG) and predominantly locates to and interacts with STAT3 in the nucleus, probably in the nuclear body structure. Overexpression of PLSCR2 attenuates ISRE-driven reporter activity, which is further aggravated by co-expression of STAT3. Moreover, PLSCR2 deficiency enhances IFN-I-induced gene expression and antiviral activity without affecting the activation or nuclear translocation of STAT1 and STAT2 or the assembly of ISGF3 complex. Instead, PLSCR2 impedes promoter occupancy by ISGF3, an effect further intensified by the presence of STAT3. Moreover, palmitoylation of PLSCR2 is required for its binding to STAT3 and for this suppressive activity. In addition, PLSCR2 also interacts with STAT2, which facilitates the suppressive effect on ISGF3-mediated transcriptional activity. Moreover, the suppressive effect of STAT2 and STAT3 is distinct, as the palmitoylation domain of PLSCR2 is dispensable. Finally, PLSCR2KO mice are generated and subjected to viral infections. PLSCR2KO mice are more resistant to VSV infection than WT control through footpad injection. Interestingly, the mutant mice are, otherwise, more susceptible to influenza virus infection through intranasal route, which may be due to enhanced inflammatory response. Indeed, in LPS-induced systemic shock assay, PLSCR2KO mice are more susceptible than WT control. Therefore, we also demonstrate a role of PLSCR2 in vivo in suppressing antiviral and inflammatory responses. Together, these results define the role of a novel STAT3-PLSCR2 axis in fine-tuning IFN-I response. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/71909 |
DOI: | 10.6342/NTU201804119 |
全文授權: | 有償授權 |
顯示於系所單位: | 免疫學研究所 |
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