GBP4通过靶向STING促进抗病毒天然免疫应答  

GBP4 promotes innate antiviral immune response by targeting STING

作　　者：金敏杰 杨琼 周卓 Jin Minjie;Yang Qiong;Zhou Zhuo(State Key Laboratory of Common Mechanism Research for Major Diseases,Suzhou Institute of Systems Medicine,Chinese Academy of Medical Sciences&Peking Union Medical College.Suzhou 215123,China)

机构地区：[1]北京协和医学院中国医学科学院系统医学研究院/苏州系统医学研究所重大疾病共性机制研究全国重点实验室,215123

出　　处：《国际病毒学杂志》2025年第1期23-27,共5页International Journal of Virology

基　　金：国家自然科学基金(31870893)。

摘　　要：目的探究鸟苷酸结合蛋白4(guanylate binding protein 4,GBP4)对于抗病毒天然免疫应答的调控及作用机制。方法构建GBP4及其酶活突变体质粒GBP4-M1(Δ60-67)、GBP4-M2(Δ82-84)和GBP4-M3(Δ112-116),通过蛋白免疫印迹和实时荧光定量PCR等实验,检测GBP4或其突变体的表达对Ⅰ型干扰素(type I interferon,IFN-I)反应的影响,并通过免疫荧光与免疫共沉淀实验验证GBP4与干扰素基因刺激因子(stimulator of interferon genes,STING)的相互作用。结果GBP4通过与STING相互作用,显著增加TANK结合激酶1(TANK-binding kinase 1,TBK1)、干扰素调节因子3(interferon regulatory factor 3,IRF3)与STING的磷酸化,IFN-I的应答以及下游干扰素刺激基因(interferon-stimulated genes,ISGs)表达也显著增多,且此作用依赖于GBP4的GTP酶活性结构域。结论GBP4通过促进环状GMP-AMP合成酶(cyclic GMP-AMP synthase,cGAS)-STING信号通路活化正向调控宿主IFN-Ⅰ反应,发挥抗病毒作用。Objective To investigate the mechanism of regulation and effects of guanylate binding protein 4(GBP4)on the innate antiviral immune response.MethodsThe plasmids expressing GBP4 and the GTPase were constructed,including activity-deficient mutants GBP4-M1(Δ60-67),GBP4-M2(Δ82-84)and GBP4-M3(Δ112-116).The effects of GBP4 or its mutants on the response of type I interferon(IFN-I)were detected by immunoblotting and quantitative real-time reverse-transcription PCR assay.The interaction between GBP4 and stimulator of interferon genes(STING)was examined by immunofluorescence and immunoprecipitation assays.ResultsBy interacting with STING,GBP4 substantially increases the phosphorylation of TANK-binding kinase 1(TBK1),interferon regulatory factor 3(IRF3),and STING.The response of IFN-I and expressions of interferon-stimulated genes(ISGs)also increased significantly,and this effect was dependent of the GTPase activity domain of GBP4.ConclusionsGBP4 exerts antiviral effects by promoting the activation of cyclic GMP-AMP synthase(cGAS)-STING signaling pathway,thereby positively regulating the host IFN-Ⅰresponse.

关 键 词：鸟苷酸结合蛋白4 Ⅰ型干扰素 干扰素基因刺激因子 

分 类 号：R51[医药卫生—内科学]