Myeloid neddylation targets IRF7 and promotes host innate immunity against RNA viruses

Neddylation, an important type of post-translational modification, has been implicated in innate and adapted immunity. But the role of neddylation in innate immune response against RNA viruses remains elusive. Here we report that neddylation promotes RNA virus-induced type I IFN production, especially IFN-alpha. More importantly, myeloid deficiency of UBA3 or NEDD8 renders mice less resistant to RNA virus infection. Neddylation is essential for RNA virus-triggered activation of Ifna gene promoters. Further exploration has revealed that mammalian IRF7undergoes neddylation, which is enhanced after RNA virus infection. Even though neddylation blockade does not hinder RNA virus-triggered IRF7 expression, IRF7 mutant defective in neddylation exhibits reduced ability to activate Ifna gene promoters. Neddylation blockade impedes RNA virus-induced IRF7 nuclear translocation without hindering its phosphorylation and dimerization with IRF3. By contrast, IRF7 mutant defective in neddylation shows enhanced dimerization with IRF5, an Ifna repressor when interacting with IRF7. In conclusion, our data demonstrate that myeloid neddylation contributes to host anti-viral innate immunity through targeting IRF7 and promoting its transcriptional activity. Author summaryWith the features of high mutation rates and fast propagation, RNA viruses remain a great challenge for the control and prevention of epidemic. Better understanding of the molecular mechanisms involved in host innate immunity against RNA viruses will facilitate the development of anti-viral drugs and vaccines. Neddylation has been implicated in innate and adapted immunity. But the role of neddylation in RNA virus-triggered type I IFN production remains elusive. Here, using mouse models with myeloid deficiency of UBA3 or NEDD8, we report for the first time that neddylation contributes to innate immunity against RNA viruses in mammals. Neddylation is indispensable for RNA virus-induced IFN-alpha production although its role in IFN-beta production is much blunted in macrophages. In mechanism, neddylation directly targets IRF7 and enhances its transcriptional activity through, at least partially, promoting its nuclear translocation and preventing its dimerization with IRF5, an Ifna repressor when interacting with IRF7. Our study provides insight into the regulation of IRF7 and innate immune signaling.