Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS

文献类型： 外文期刊

第一作者： Liuyu, Tianzi

作者： Liuyu, Tianzi;Yu, Keying;Ye, Liya;Zhang, Zhidong;Zhang, Man;Ren, Yujie;Cai, Zeng;Zhong, Bo;Liuyu, Tianzi;Yu, Keying;Ye, Liya;Zhang, Zhidong;Zhang, Man;Ren, Yujie;Cai, Zeng;Zhong, Bo;Zhu, Qiyun;Lin, Dandan

作者机构：

期刊名称：CELL RESEARCH （ 影响因子：25.617； 五年影响因子：25.924 ）

ISSN： 1001-0602

年卷期： 2019 年 29 卷 1 期

页码：

收录情况： SCI

摘要： 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-kappa B, expression of their downstream target genes, and potentiates VSV replication in vitro and in vivo. Consistently, Cre-ER Otud4(fl/fl) or Lyz2-Cre Otud4(fl/fl) mice 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.

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