OTUB1 Is a Key Regulator of RIG-I-Dependent Immune Signaling and Is Targeted for Proteasomal Degradation by Influenza A NS1
OTUB1 Is a Key Regulator of RIG-I-Dependent Immune Signaling and Is Targeted for Proteasomal Degradation by Influenza A NS1
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DOI：
10.1016/j.celrep.2020.01.015
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发表时间：
2020-02-04
期刊：
影响因子：
8.8
通讯作者：
Sanyal, Sumana
中科院分区：
文献类型：
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作者：
Jahan, Akhee Sabiha;Biquand, Elise;Sanyal, Sumana
去泛素化酶（DUBs）在宿主免疫和病毒发病机制的交叉点调节关键信号传导途径。虽然RIG-I的激活在很大程度上依赖于泛素化，DUBs调节这一途径的系统分析尚未进行。使用泛素C-末端亲电试剂，我们分析了在甲型流感病毒（IAV）感染期间起作用的DUB，并分离出OTUB 1作为RIG-I依赖性抗病毒反应的关键调节因子。感染后，OTUB 1与RIG-1、病毒PB 2和NS 1一起从细胞核重新定位到线粒体、膜。其表达依赖于干扰素刺激和IAV触发的降解的竞争效应。OTUB 1通过K48多聚泛素水解和与UBCH 5c形成E2抑制复合物的双重机制激活RIG-I。我们在包含[S-35] IRF 3、纯化的RIG-I、线粒体的无细胞系统中重建了该机制！膜和表达OTUB 1变体的胞质溶胶。一系列IAV NS 1蛋白触发OTUB 1的蛋白酶体降解，拮抗RIG-I信号级联和抗病毒反应。
Deubiquitylases (DUBs) regulate critical signaling pathways at the intersection of host immunity and viral pathogenesis. Although RIG-I activation is heavily dependent on ubiquitylation, systematic analyses of DUBs that regulate this pathway have not been performed. Using a ubiquitin C-terminal electrophile, we profile DUBs that function during influenza A virus (IAV) infection and isolate OTUB1 as a key regulator of RIG-I-dependent antiviral responses. Upon infection, OTUB1 relocalizes from the nucleus to mitochondria, membranes together with RIG-I, viral PB2, and NS1. Its expression depends on competing effects of interferon stimulation and IAV-triggered degradation. OTUB1 activates RIG-I via a dual mechanism of K48 polyubiquitin hydrolysis and formation of an E2-repressive complex with UBCH5c. We reconstitute this mechanism in a cell-free system comprising [S-35]IRF3, purified RIG-I, mitochondria! membranes, and cytosol expressing OTUB1 variants. A range of IAV NS1 proteins trigger proteasomal degradation of OTUB1, antagonizing the RIG-I signaling cascade and antiviral responses.