FKBP8 Inhibits Virus-Induced RLR-VISA Signaling

Recent studies have shown that post-translational modifications of proteins,such as phosphorylation and ubiquitination,are widely involved in the regulation of viral-induced type I interferon production.The mitochondrial antiviral signaling protein(VISA),as an important adaptor protein,plays an important role in regulating the host’s natural immune signaling pathway.Proteins interacting with VISA were searched by yeast two-hybrid screening.In this screening,we found that FKBP8(FK506-binding protein 8)is able to negatively regulate the RLR(RIG-I like receptor)signaling pathway.A number of literatures have reported that FKBP family proteins play a role in regulating viral-induced immune responses.Our experiments confirmed that overexpression of FKBP8 can significantly down-regulate the activation of promoter IFN-β(interferons β)、 transcription factors NF-κB(nuclear factor κ-light chain enhancer of activated B cells)and ISRE(IFN-stimulated response element)induced by Sendai virus;while down-regulation of FKBP8 endogenous gene expression can be specifically enhanced the activation of promoter IFN-β、transcription factors NF-κB and ISRE induced by Sendai virus.The results of co-immunoprecipitation showed that FKBP8 can specifically interact with RIG-I(retinoic acid inducible protein 1),VISA and IRF3(IFN regulatory factor 3),and this interaction is more obvious with the stimulation of SeV.Meanwhile,we found that FKBP8 negatively regulates VISA and TBK1(TANK binding kinase 1)-mediated RLR signaling pathway,and FKBP8 promotes the degradation of TBK1,RIG-I and TRAF3(TNF receptor-associated factor 3)in the RLR pathway.In addition,FKBP8 potentiates the polyubiquitination of RIG-I and TBK1 induced by Sendai virus.In contrast,when down-regulating the expression of the FKBP8 endogenous gene,FKBP8 specifically inhibits the polyubiquitination of RIG-I and TBK1 induced by Sendai virus.Taken together,our study shows that FKBP8 promotes the degradation of TBK1 and RIG-I by promoting polyubiquitination of RIG-I and TBK1.Our research has unanswered questions.For example,is there a synergy between TRAF5(TNF receptor-associated factor 5)and FKBP8? or is TRAF5 an extra role for FKBP8? Our study demonstrates that FKBP8 acts as an important negative regulator in the RLR antiviral innate immune signaling pathway.Our study only reveals the role of FKBP8 in the RLR pathway,and a comprehensive understanding of its function remains to be further studied.