Forkhead box O1-mediated ubiquitination suppresses RIG-I-mediated antiviral immune responses.

RNA virus infection activates the RIG-I-like Receptor (RLR) signaling pathway to produce type I interferons (IFNs), the key components of the antiviral immune response. Forkhead box O1 (FoxO1) is a host transcription factor that participates in multiple biological processes. In this study, FoxO1 was identified as a critical negative regulator of RIG-I-triggered signaling. FoxO1 promoted Sendai virus (SeV) replication and downregulated type I IFN production. Upon SeV infection, FoxO1 suppressed K63-linked ubiquitination of TRAF3 and the interaction between TRAF3 and TBK1, after which the production of type I IFNs via the interferon regulatory transcription factor 3 (IRF3) pathways was reduced. In addition, FoxO1 destabilized IRF3 by facilitating E3 ligase TRIM22- or TRIM21-mediated K48-linked ubiquitination of IRF3. Moreover, the inhibitory effect of FoxO1 was found to depend on its DNA binding domain (DBD). Thus, our findings highlight novel important roles of FoxO1 in controlling RLR-mediated antiviral innate immunity.