期刊
CELL RESEARCH
卷 29, 期 1, 页码 67-79出版社
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/s41422-018-0107-6
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资金
- Ministry of Science and Technology of China [2014CB542601]
- Natural Science Foundation of China [31521091, 31601131, 31671454, 31622036]
- National Natural Science Foundation of Hubei Province [2018CFA016]
- Wuhan University [2042017kf0199, 2042017kf0242]
- State Key Laboratory of Veterinary Etiological Biology [SKLVEB2017KFKT004]
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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