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MAVS activates TBK1 and IKKε through TRAFs in NEMO dependent and independent manner

Run Fang1,2,3, Qifei Jiang1,2,3, Xiang Zhou1,2,3

  • 1Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China.

Plos Pathogens
|November 11, 2017
PubMed

Insights

Mitochondrial antiviral-signaling protein (MAVS) activates innate immunity via TRAF proteins, not TBK1-binding proteins. TRAF E3 ligase activity and NEMO are crucial for RNA virus response signaling.

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • Mitochondrial antiviral-signaling protein (MAVS) is key in RIG-I-like receptor signaling during RNA virus infections.
  • The precise mechanisms of MAVS activation of TBK1 and IKKα/β remain incompletely understood.
  • Previous studies suggested roles for NEMO or TBK1-binding proteins like TANK, NAP1, and SINTBAD.

Purpose of the Study:

  • To elucidate the mechanism of MAVS-mediated activation of downstream signaling components, specifically TBK1 and IKKα/β.
  • To determine the role of TNF receptor-associated factors (TRAFs) and NEMO in MAVS signaling.
  • To investigate the necessity of TRAFs' E3 ligase activity and NEMO activation for antiviral responses.

Main Methods:

  • Utilized TRAF2-/-3-/-5-/-6-/- cells to assess RNA virus responses.
  • Investigated direct interactions between TRAFs and TBK1/IKKε using domain analysis.
  • Analyzed the requirement of TRAFs' E3 ligase activity and NEMO for NF-κB and TBK1/IKKε activation.
  • Examined the role of IKKα/β in TBK1/IKKε activation through phosphorylation.

Main Results:

  • MAVS-mediated innate immune activation is dependent on TRAFs and partially on NEMO, but independent of TBK1-binding proteins.
  • TRAFs directly interact with TBK1/IKKε, mediating their recruitment to MAVS.
  • TRAF2-/-3-/-5-/-6-/- cells exhibited a complete loss of RNA virus responses.
  • TRAFs' E3 ligase activity is essential for NEMO activation, leading to NF-κB and TBK1/IKKε activation.
  • NEMO-activated IKKα/β are critical for TBK1/IKKε activation via phosphorylation.
  • Individual TRAFs differentially regulate TBK1/IKKε activation, fine-tuning antiviral immunity.

Conclusions:

  • TRAFs, not TBK1-binding proteins, are essential for MAVS-mediated antiviral signaling.
  • TRAF E3 ligase activity and subsequent NEMO activation are critical for initiating downstream antiviral responses.
  • Differential contributions of individual TRAFs allow for the fine-tuning of innate antiviral immunity.

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