Prof. Zhengfan Jiang published a paper on PLOS Pathogens.
Innate immunity is the first line of defense against virus infection. RIG-I-like receptors (RLRs) recognize various viral RNA from RNA viruses and initiate host antiviral responses to produce type I interferons (IFNs) and other cytokines. RLRs sense distinct types of viruses by sharing a common adaptor protein called mitochondrial antiviral-signaling protein (MAVS). Although it has been well studied how RLRs recruit and activate MAVS upon virus infection, it remains to be elucidated how MAVS activates its downstream components, including kinases TBK1/IKKε and the IKK complex. Here, by using TANK−/−NAP1−/−SINTBAD−/−, TRAF2−/−3−/−5−/−6−/− andTRAF2−/−3−/−5−/−6−/−NEMO−/− 293T cells combined with reconstitution experiments, we discovered that MAVS recruited TBK1/IKKε via TRAFs through pre-associated TRAFs-TBK1/IKKε complex. TBK1/IKKε activation required both TRAFs-mediated TBK1 autophosphorylation and TRAFs-NEMO-IKKβ-mediated TBK1 phosphorylation. We demonstrated that TRAFs’ E3 ligase activity was solely required for NEMO and IKKα/β activation. IKKα/β were crucial for both TBK1 and NF-κB activation. Our results thus demonstrated that MAVS activates TBK1/IKKε through TRAFs in both NEMO-dependent and independent manner. Importantly, a minimal amount of IFNs was produced independent of NF-κB activation during virus infection and that individual TRAFs differently mediated TBK1/IKKε activation, thus fine-tuned antiviral immunity under physiological conditions.
Original link: http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006720
