RNF19a inhibits antiviral immune response to RNA viruses through degradation of TBK1

•The expression of RNF19a is increased in macrophages upon virus infection.•RNF19a selectively inhibits type I interferon production upon RNA virus infection.•RNF19a inhibits the RIG-I signaling upon RNA virus infection.•RNF19a promotes the degradation of TBK1 through K48-linked ubiquitination. TANK-binding kinase 1 (TBK1) plays a pivotal role in antiviral innate immunity. TBK1 mediates the activation of interferon regulatory factor (IRF) 3, leading to the induction of type I IFNs (IFN-α/β) and of NF-κB signal transduction following viral infections. TBK1 must be tightly regulated to effectively control viral infections and maintain immune homeostasis. Here, we found that E3 ubiquitin ligase RNF19a mediated K48-linked ubiquitination and proteasomal degradation of TBK1. Specifically, the silence of RNF19a enhanced the production of type I interferons and suppressed RNA viral replication. Our results uncover that RNF19a acts as a negative mediator in the RIG-I signaling pathway to attenuate antiviral immune responses and suggest RNF19a as a potential therapy target in clinical infectious and inflammatory diseases.