Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS
Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS
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病毒感染诱导 OTUD4 通过去泛素化和稳定 MAVS 促进抗病毒反应
DOI：
10.1038/s41422-018-0107-6
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发表时间：
2019-01-01
期刊：
影响因子：
44.1
通讯作者：
Zhong, Bo
中科院分区：
文献类型：
--
作者：
Liuyu, Tianzi;Yu, Keying;Zhong, Bo
适配器蛋白MAVS（也称为VISA、Cardif和IPS-1）的活性和稳定性受到泛素化的广泛调节，它介导细胞抗病毒反应。然而，MAVS去泛素化的过程尚不清楚。在这里，我们报道卵巢肿瘤家族去泛素酶4 （OTUD4）靶向MAVS去泛素化。病毒感染导致OTUD4的irf3 /7依赖性上调，OTUD4与MAVS相互作用去除k48连接的多泛素链，从而维持MAVS的稳定性并促进先天抗病毒信号传导。敲除或敲低OTUD4会损害RNA病毒引发的IRF3和NF-κB的激活及其下游靶基因的表达，并增强VSV在体外和体内的复制。与对照组相比，Cre-EROtud4fl/flor Lyz2-CreOtud4fl/flmice产生的I型干扰素和促炎细胞因子水平降低，对VSV感染的敏感性增加。此外，将MAVS重组到otud4缺陷细胞中可以恢复病毒诱导的下游基因表达和细胞抗病毒反应。总之，我们的发现揭示了OTUD4在病毒触发的信号传导中的重要作用，并有助于理解去泛素化介导的先天抗病毒反应调节。
The activity and stability of the adapter protein MAVS (also known as VISA, Cardif and IPS-1), which critically mediates cellular antiviral responses, are extensively regulated by ubiquitination. However, the process whereby MAVS is deubiquitinated is unclear. Here, we report that the ovarian tumor family deubiquitinase 4 (OTUD4) targets MAVS for deubiquitination. Viral infection leads to the IRF3/7-dependent upregulation of OTUD4 which interacts with MAVS to remove K48-linked polyubiquitin chains, thereby maintaining MAVS stability and promoting innate antiviral signaling. Knockout or knockdown of OTUD4 impairs RNA virus-triggered activation of IRF3 and NF-κB, expression of their downstream target genes, and potentiates VSV replication in vitro and in vivo. Consistently, Cre-EROtud4fl/flor Lyz2-CreOtud4fl/flmice produce decreased levels of type I interferons and proinflammatory cytokines and exhibit increased sensitivity to VSV infection compared to their control littermates. In addition, reconstitution of MAVS into OTUD4-deficient cells restores virus-induced expression of downstream genes and cellular antiviral responses. Together, our findings uncover an essential role of OTUD4 in virus-triggered signaling and contribute to the understanding of deubiquitination-mediated regulation of innate antiviral responses.