Abstract
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-α. 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.
Highlights
Innate immunity is the body’s first line of defense against the invasion of viruses, of which macrophages are key components to inhibit the invasion and replication of viruses
Neddylation is indispensable for RNA virus-induced IFN-α production its role in IFN-β production is much blunted in macrophages
Even though neddylation suppression by MLN4924 treatment was reported to result in the apoptosis of macrophages in vitro [29], flow cytometry analysis revealed that Uba3ΔMye and Nedd8ΔMye mice and their control (Uba3F/F and Nedd8F/F) littermates exhibited similar percentages of F4/80+CD11b+ macrophages in the peripheral blood, bone marrow, spleen, and peritoneal cavity (S1 Fig)
Summary
Innate immunity is the body’s first line of defense against the invasion of viruses, of which macrophages are key components to inhibit the invasion and replication of viruses. After the recognition of viral nucleic acids, interferon regulatory factors (IRFs, mainly IRF3 and IRF7), nuclear factor κB (NF-κB), and activating protein 1 (AP1) are activated by innate immune signaling to induce the production of type I interferons (IFNs, IFN-α and IFN-β) and inflammatory cytokines [1,2,3,4]. Under steady state, unphosphorylated IRF3 and IRF7 stay in the cytoplasm and NF-κB is sequestered in the cytoplasm by inhibitor of κB (IκB) proteins. Upon phosphorylated by the IκB kinase (IKK)-related kinases, TANK-binding kinase 1 (TBK1) and IKKi, IRF3 and IRF7 undergo dimerization and nuclear translocation [5,6,7,8]. Phosphorylated IκB proteins undergo ubiquitin-mediated degradation, thereby releasing NF-κB. In most cell types including macrophages, IRF3 is constitutively expressed while IRF7 is expressed at a low level under steady state but is strongly induced by type I IFNs [8]
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