Demalonylation of DDX3 by Sirtuin 5 promotes antiviral innate immune responses.
Demalonylation of DDX3 by Sirtuin 5 promotes antiviral innate immune responses.
复制标题
Sirtuin 5 对 DDX3 的去丙酰化促进抗病毒先天免疫反应
作者：
He X;Li T;Qin K;Luo S;Li Z;Ji Q;Song H;He H;Tang H;Han C;Li H;Luo Y
基本原理：抗病毒抗体通过检测病毒病原体相关的分子模式来防御病毒感染，并通过TBK 1-IRF 3信号转导激活抗病毒先天免疫。然而，潜在的分子机制仍不清楚。方法：将靶向Sirt 1 -7的siRNA转染巨噬细胞，筛选其抗病毒功能。将Sirt 5缺陷型小鼠或巨噬细胞进行病毒感染，通过检测细胞因子、病毒复制和存活率来评估Sirt 5的体内和体外功能。采用免疫沉淀、WesternBlot和荧光素酶报告基因分析等方法研究其分子机制。结果如下：本研究对Sirtuin家族的7个成员进行了功能筛选，发现Sirtuin 5（Sirt 5）促进抗病毒信号传导和应答。Sirt 5缺陷通过减少TBK 1-IRF 3活化和I型IFN产生导致病毒感染后体内和体外抗病毒先天免疫减弱。Sirt 5过表达增加抗病毒天然免疫。机制研究表明，Sirt 5与DDX 3相互作用并使DDX 3脱丙二酸，这对TBK 1-IRF 3活化至关重要。DDX 3的脱丙二酰赖氨酸位点（K66、K130和K162）的突变增加了ifnβ的转录。DDX 3的赖氨酸118位的乙酰化正调控ifnβ的转录，而Sirt 5不能使该位点脱乙酰化。结论：Sirt 5通过去丙二酸化DDX 3增加TBK 1信号传导来促进抗RNA和DNA病毒先天免疫反应，这确定了抗病毒先天免疫反应的一种新型调节途径。
Rationale: Hosts defend against viral infection by sensing viral pathogen-associated molecular patterns and activating antiviral innate immunity through TBK1-IRF3 signaling. However, the underlying molecular mechanism remains unclear. Methods: SiRNAs targeting Sirt1-7 were transfected into macrophages to screen the antiviral function. Sirt5 deficient mice or macrophages were subjected to viral infection to assess in vivo and in vitro function of Sirt5 by detecting cytokines, viral replicates and survival rate. Immunoprecipitation, WesternBlot and luciferase reporter assay were used to reveal molecular mechanism. Results: In this study, we functionally screened seven Sirtuin family members, and found that Sirtuin5 (Sirt5) promotes antiviral signaling and responses. Sirt5 deficiency leads to attenuated antiviral innate immunity in vivo and in vitro upon viral infection by decreasing TBK1-IRF3 activation and type I IFN production. Sirt5 overexpression increased antiviral innate immunity. Mechanism investigation revealed that Sirt5 interacts with DDX3 and demalonylates DDX3, which is critical for TBK1-IRF3 activation. Mutation of the demalonylation lysine sites (K66, K130, and K162) of DDX3 increased ifnβ transcription. Furthermore, the acetylation on lysine 118 of DDX3 positively regulated ifnβ transcription, whereas Sirt5 could not deacetylate this site. Conclusion: Sirt5 promotes anti- RNA and DNA virus innate immune responses by increasing TBK1 signaling through demalonylating DDX3, which identifies a novel regulatory pathway of antiviral innate immune response.
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影响因子：
16
作者：
Nishida Y;Rardin MJ;Carrico C;He W;Sahu AK;Gut P;Najjar R;Fitch M;Hellerstein M;Gibson BW;Verdin E
通讯作者：
Verdin E
影响因子：
46.9
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影响因子：
64.5
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通讯作者：
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影响因子：
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影响因子：
5.4
作者：
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