线粒体抗病毒信号蛋白MAVS磷酸化调控其抗病毒活性  

Phosphorylation of the mitochondrial antiviral signaling proteinMAVS regulates its antiviral activity

作　　者：汪婷婷 徐昌志 朱林 刘萱 WANG Tingting;XU Changzhi;ZHU Lin;LIU Xuan(Institutes of Physical Science and Information Technology,Anhui University,Hefei 230601,China;Academy of Military Medical Sciences,Beijing 100850,China)

机构地区：[1]安徽大学物质科学与信息技术研究院,合肥230601 [2]军事医学研究院,北京100850

出　　处：《生物学杂志》2025年第2期24-32,共9页Journal of Biology

基　　金：国家自然科学基金项目(82372255)。

摘　　要：线粒体抗病毒信号蛋白(MAVS)是宿主应对RNA病毒产生先天性免疫信号途径中的重要接头蛋白,主要在天然免疫和炎症反应方面起重要调控作用。MAVS的表达和功能受转录和翻译后修饰两种机制的调控,其中,磷酸化和泛素化在调节MAVS的转运、功能和稳定性等方面起重要作用。为了进一步研究MAVS磷酸化对细胞产生IFN-β和TNF-α的水平影响,利用串联质谱技术发现了7个尚未被报道的MAVS磷酸化位点,包括pS193、pS226、pS238、pS246、pS249、pT252和pT370。随后,将上述磷酸化位点突变为丙氨酸(A)构建磷酸化缺陷突变体,发现MAVS T370A突变可显著抑制MAVS信号通路下游IFN-β和核调节因子-κB(NF-κB)报告基因的转录活性,进而下调IFN-β和TNF-α的表达,抑制细胞抗病毒反应。结果提示,T370位点作为尚未报道的MAVS磷酸化位点,在宿主先天免疫信号通路中发挥重要作用。进一步解析介导T370位点磷酸化的激酶,对揭示先天性免疫稳态维持和宿主抗病毒分子机制将具有重要意义。Mitochondrial antiviral signaling protein(MAVS)is an important adaptor protein in the host innate immunity pathway in response to RNA viruses,playing important regulatory roles in innate immune and inflammatory responses.The expression and the function of MAVS are regulated by two mechanisms,namely transcription and post-translational modification,and phosphorylation and ubiquitination play important roles in regulating the transport,function and stability of MAVS.In order to further investigate the effect of MAVS phosphorylation on the levels of IFN-βand TNF-αproduction in cells,seven previously unreported MAVS phosphorylation sites,including pS193,pS226,pS238,pS246,pS249,pT252,and pT370,were identified by tandem mass spectrometry.Subsequently,the above phosphorylation sites were mutated into alanine(A)to construct a phosphorylation-deficient mutant.It was found that MAVS T370A mutation could significantly inhibit the transcriptional activity of IFN-βand NF-κB reporter genes downstream of the MAVS signaling pathway,and then down-regulate the expression of IFN-βand TNF-α,and inhibit the antiviral response of cells.These results suggested that T370,as an unreported phosphorylation site of MAVS,played an important role in the host innate immune signaling pathway.Further elucidation of kinases mediating phosphorylation at T370 will be of great significance for revealing the molecular mechanism of innate immune homeostasis maintenance and host antiviral activity.

关 键 词：线粒体抗病毒信号蛋白 先天性免疫 炎症反应 IFN-Β 核调节因子-κB 磷酸化 

分 类 号：Q786[生物学—分子生物学]