Black carp OTUD1 negatively regulates antiviral innate immunity via deubiquitination and degradation of IRF3/7.

IRF3 and IRF7 function importantly in type I interferon production. Ovarian tumor deubiquitinase 1 (OTUD1) is a critical member of OUT deubiquitinases, which has been identified as a negative regulator in IRF3-mediated interferon signaling in mammals. However, the role of teleost OTUD1 in the immunity remains unclear. In this study, black carp (Mylopharyngodon piceus) OTUD1 (bcOTUD1) was cloned and identified, distributed in the nucleus and cytoplasm, and involved in virus-induced innate immune response. Overexpression of bcOTUD1 inhibits bcIRF3/7-mediated interferon production and antiviral ability, while knockdown bcOTUD1 promotes host antiviral capacity. In addition, bcOTUD1 could degrade bcIRF3/7 protein levels, while proteasome inhibitor MG132, lysosome inhibitor chloroquine and autophagy inhibitor 3-MA are able to restore this degradation. Co-immunoprecipitation assay has revealed that bcOTUD1 interacts with bcIRF3/7, and removes K63-linked ubiquitination of bcIRF3 and K48- and K63-linked ubiquitination of bcIRF7. To conclude, our research has brought to light for the first time in teleost that OTUD1 degrade IRF3/7 through decreasing their ubiquitination, thereby restraining IRF3/7-mediated antiviral immune response, which provides an important reference for the study of teleost interferon signaling.