MAVS activates TBK1 and IKK? through TRAFs in NEMO dependent and independent manner.

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 IKK?/?, 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/IKK? by TRAFs that were pre-associated with TBK1/IKK? via direct interaction between the coiled-coil domain of TRAFs and the SDD domain of TBK1/IKK?. 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-?B and TBK1/IKK? activation. NEMO-activated IKK?/? were important for TBK1/IKK? activation through IKK?/?-mediated TBK1/IKK? phosphorylation. Moreover, individual TRAFs differently mediated TBK1/IKK? activation and thus fine-tuned antiviral immunity under physiological conditions.

SUBMITTER: Fang R 

PROVIDER: S-EPMC5699845 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature