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IFN-induced TPR protein IFIT3 potentiates antiviral signaling by bridging MAVS and TBK1

Xin-Yi Liu1, Wei Chen, Bo Wei

  • 1Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

Journal of Immunology (Baltimore, Md. : 1950)
|August 5, 2011
PubMed

Insights

IFN-induced protein with tetratricopeptide repeats 3 (IFIT3) bridges mitochondrial antiviral signaling (MAVS) to TBK1 kinase, enhancing antiviral immune responses. This discovery reveals IFIT3

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • Intracellular RNA viruses trigger innate immunity via RIG-I/MDA5 receptors.
  • Activation of mitochondrial antiviral signaling (MAVS) complex leads to TBK1 and IRF3 activation.
  • The precise mechanism linking MAVS to TBK1/IRF3 activation remains unclear.

Purpose of the Study:

  • To investigate the role of IFN-induced protein with tetratricopeptide repeats 3 (IFIT3) in the MAVS-mediated antiviral signaling pathway.
  • To elucidate the molecular mechanism by which IFIT3 modulates TBK1/IRF3 activation.
  • To characterize IFIT3 as a potential regulator of innate antiviral immunity.

Main Methods:

  • Quantitative analysis of IFIT3 induction upon RNA virus infection.
  • Gain-of-function (ectopic expression) and loss-of-function (knockdown) studies of IFIT3.
  • Co-immunoprecipitation assays to identify protein-protein interactions between IFIT3 and TBK1.
  • Assessment of TBK1 and IRF3 activation by measuring phosphorylation levels.
  • Evaluation of host antiviral gene expression and viral replication.

Main Results:

  • IFIT3 expression is significantly upregulated during RNA virus infection.
  • Ectopic IFIT3 enhances, while IFIT3 knockdown impairs, IRF3-mediated gene expression.
  • IFIT3 directly interacts with TBK1 via its tetratricopeptide repeat motif, bridging TBK1 to MAVS.
  • Disruption of the IFIT3-TBK1 interaction attenuates TBK1 and IRF3 activation.
  • IFIT3 presence boosts, while its absence cripples, host antiviral responses.

Conclusions:

  • IFIT3 is a crucial host factor induced by RNA viruses.
  • IFIT3 acts as a molecular bridge, connecting MAVS to TBK1 for efficient antiviral signaling.
  • IFIT3 plays a significant role in modulating innate immunity and enhancing antiviral responses.
  • This study reveals a novel function for IFIT family proteins in innate immunity.

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