E3 ligase TRIM65 is essential for MDA5-mediated antiviral innate immunity
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- 英文论文题名：E3 ligase TRIM65 is essential for MDA5-mediated antiviral innate immunity
- 论文作者：Lang xueting ; Tang tiantian
- 英文论文作者：Lang xueting ; Tang tiantian ; Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease ; CAS center for Excellence in Molecular Cell Sciences ; School of Life Sciences and Medical Center ; University of Science and Technology of China
- 年：2016
- 作者机构：Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease,CAS center for Excellence in Molecular Cell Sciences,School of Life Sciences and Medical Center,University of Science and Technology of China;
- 英文论文关键词：TRIM65 ; MDA-5 ; ubiquitination ; oligomerization
- 会议召开时间：2016-11-04
- 会议录名称：第十一届全国免疫学学术大会壁报交流集
- 英文会议录名称：Proceedings of 2016 CSI Congress on Immunology
- 语种：英文
- 分类号：R392
- 学会代码：IGMD
- 会议名称：第十一届全国免疫学学术大会
- 会议地点：中国安徽合肥
- 主办单位：中国免疫学会
- 学会名称：中国免疫学会
- 页数：2
- 文件大小：1332k
- 原文格式：D
- 会议级别：全国
摘要
MDA5 plays a critical role for antiviral innate immunity by functioning as a cytoplasmic ds RNA sensor which can activate the type I interferon signaling pathway,but the mechanism for the activation of MDA5 is poorly understood.The aim of our study is to search the unknown mechanism of the activation of MDA-5 signaling.To search for MDA5 binding partners,we used mass spectrometry and co-immunoprecipitation assay to identify the proteins associated with MDA5 and found that E3 ligase TRIM65 had the highest number of matched peptides in the precipitates.To examine the role of TRIM65 in EMCV-induced MDA5 activation,we generated Trim65-deficient mice using transcription activator-like effector nuclease(TALEN)-based genome editing technology.Here we show that TRIM65 specifically interacts with MDA5 and promotes K63-linked ubiquitination of MDA5 at lysine 743,which is critical for MDA5 oligomerization and activation.We found that Trim65 deficiency abolishes MDA5 agonist or encephalomyocarditis virus(EMCV)-induced IRF3 activation and type I interferon production,but has no effect for RIG-I,TLR3 or c GAS sginaling pathway.Importantly,Trim65-/-mice are susceptible to EMCV infection andproduce much less type I interferon in vivo compared with control.Taken together,we searched for previously unknown MDA5 binding partners and identified a MDA5 binding protein TRIM65,which plays an essential role for MDA5 activation by promoting its ubiquitination and oligomerization.
MDA5 plays a critical role for antiviral innate immunity by functioning as a cytoplasmic ds RNA sensor which can activate the type I interferon signaling pathway,but the mechanism for the activation of MDA5 is poorly understood.The aim of our study is to search the unknown mechanism of the activation of MDA-5 signaling.To search for MDA5 binding partners,we used mass spectrometry and co-immunoprecipitation assay to identify the proteins associated with MDA5 and found that E3 ligase TRIM65 had the highest number of matched peptides in the precipitates.To examine the role of TRIM65 in EMCV-induced MDA5 activation,we generated Trim65-deficient mice using transcription activator-like effector nuclease(TALEN)-based genome editing technology.Here we show that TRIM65 specifically interacts with MDA5 and promotes K63-linked ubiquitination of MDA5 at lysine 743,which is critical for MDA5 oligomerization and activation.We found that Trim65 deficiency abolishes MDA5 agonist or encephalomyocarditis virus(EMCV)-induced IRF3 activation and type I interferon production,but has no effect for RIG-I,TLR3 or c GAS sginaling pathway.Importantly,Trim65-/-mice are susceptible to EMCV infection andproduce much less type I interferon in vivo compared with control.Taken together,we searched for previously unknown MDA5 binding partners and identified a MDA5 binding protein TRIM65,which plays an essential role for MDA5 activation by promoting its ubiquitination and oligomerization.
MDA5 plays a critical role for antiviral innate immunity by functioning as a cytoplasmic ds RNA sensor which can activate the type I interferon signaling pathway,but the mechanism for the activation of MDA5 is poorly understood.The aim of our study is to search the unknown mechanism of the activation of MDA-5 signaling.To search for MDA5 binding partners,we used mass spectrometry and co-immunoprecipitation assay to identify the proteins associated with MDA5 and found that E3 ligase TRIM65 had the highest number of matched peptides in the precipitates.To examine the role of TRIM65 in EMCV-induced MDA5 activation,we generated Trim65-deficient mice using transcription activator-like effector nuclease(TALEN)-based genome editing technology.Here we show that TRIM65 specifically interacts with MDA5 and promotes K63-linked ubiquitination of MDA5 at lysine 743,which is critical for MDA5 oligomerization and activation.We found that Trim65 deficiency abolishes MDA5 agonist or encephalomyocarditis virus(EMCV)-induced IRF3 activation and type I interferon production,but has no effect for RIG-I,TLR3 or c GAS sginaling pathway.Importantly,Trim65-/-mice are susceptible to EMCV infection andproduce much less type I interferon in vivo compared with control.Taken together,we searched for previously unknown MDA5 binding partners and identified a MDA5 binding protein TRIM65,which plays an essential role for MDA5 activation by promoting its ubiquitination and oligomerization.
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