Abstract
Mitochondrial antiviral-signaling protein (MAVS) transmits signals from RIG-I-like receptors after RNA virus infections. However, the mechanism by which MAVS activates downstream components, such as TBK1 and IKKα/β, is unclear, although previous work suggests the involvement of NEMO or TBK1-binding proteins TANK, NAP1, and SINTBAD. Here, we report that MAVS-mediated innate immune activation is dependent on TRAFs, partially on NEMO, but not on TBK1-binding proteins. MAVS recruited TBK1/IKKε by TRAFs that were pre-associated with TBK1/IKKε via direct interaction between the coiled-coil domain of TRAFs and the SDD domain of TBK1/IKKε. TRAF2−/−3−/−5−/−6−/− cells completely lost RNA virus responses. TRAFs’ E3 ligase activity was required for NEMO activation by synthesizing ubiquitin chains that bound to NEMO for NF-κB and TBK1/IKKε activation. NEMO-activated IKKα/β were important for TBK1/IKKε activation through IKKα/β-mediated TBK1/IKKε phosphorylation. Moreover, individual TRAFs differently mediated TBK1/IKKε activation and thus fine-tuned antiviral immunity under physiological conditions.
Highlights
IntroductionRIG-I-like receptors (RLRs), including RIG-I, MDA5 and LGP2, detect both viral doublestranded RNA (dsRNA) and single-stranded RNA without the 5’-7-methylguanosine cap in the cytoplasm [2,3,4]
The innate immune system is the first line of defense against microbial infection
By using TANK−/−NAP1−/−SINTBAD−/−, TRAF2−/−3−/−5−/−6−/− and TRAF2−/−3−/−5−/−6−/−NEMO−/− 293T cells combined with reconstitution experiments, we discovered that mitochondrial antiviral-signaling protein (MAVS) recruited
Summary
RIG-I-like receptors (RLRs), including RIG-I, MDA5 and LGP2, detect both viral doublestranded RNA (dsRNA) and single-stranded RNA without the 5’-7-methylguanosine cap in the cytoplasm [2,3,4]. The exposed CARD domains of RIG-I and MDA5 subsequently bind to unanchored K63 polyubiquitin chains and form oligomers [19, 20]. The latter gain a high capacity of activating MAVS by inducing MAVS polymerization, presumably through CARD-CARD interactions [21,22,23,24]. Phosphorylated MAVS binds to a positively charged surface of IRF3, thereby recruiting IRF3 for its phosphorylation and activation by TBK1
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