p38 inhibition provides anti-DNA virus immunity by regulation of USP21 phosphorylation and STING activation

Stimulator of IFN genes (STI N G) is a central adaptor protein that mediates the innate immune responses to DNA virus infection. Although ubiquitination is essential for STI N G function, how the ubiquitination/deubiquitination system is regulated by virus infection to control STI N G activity remains unknown. In this study, we found that USP21 is an important deubiquitinating enzyme for STI N G and that it negatively regulates the DNA virus-induced production of type I interferons by hydrolyzing K27/63-linked polyubiquitin chain on STI N G. HSV-1 infection recruited USP21 to STI N G at late stage by p38-mediated phosphorylation of USP21 at Ser538. Inhibition of p38 MAPK enhanced the production of IFNs in response to virus infection and protected mice from lethal HSV-1 infection. Thus, our study reveals a critical role of p38-mediated USP21 phosphorylation in regulating STI N G-mediated antiviral functions and identifies p38-USP21 axis as an important pathway that DNA virus adopts to avoid innate immunity responses.