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An alternative splicing isoform of MITA antagonizes MITA-mediated induction of type I IFNs

Honghe Chen1, Rongjuan Pei, Wandi Zhu

  • 1State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China;

Journal of Immunology (Baltimore, Md. : 1950)
|January 7, 2014
PubMed

Insights

A newly identified MITA-related protein (MRP) isoform inhibits type I interferon production by disrupting MITA-TBK1 interactions. MRP acts as a dominant negative regulator, impacting innate immune responses differently based on viral infection type.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Mediator of IFN regulatory transcription factor 3 activation (MITA) is crucial for type I interferon induction.
  • Alternative splicing generates protein isoforms with potentially novel functions.

Purpose of the Study:

  • To identify and characterize a novel alternatively spliced isoform of MITA.
  • To investigate the functional role of this new isoform in innate immune signaling pathways.

Main Methods:

  • Identification of MITA-related protein (MRP) via alternative splicing.
  • Expression analysis of MRP in various tissues and cell lines.
  • Functional assays involving overexpression of MRP to assess its impact on IFN-β promoter activation and protein-protein interactions (MITA-TBK1, MRP-iκB kinase).

Main Results:

  • MRP, an isoform lacking exon 7, was identified and expressed in multiple tissues.
  • MRP inhibited MITA-mediated IFN-β promoter activation by Sendai virus and cGAMP but enhanced it during HSV-1 infection.
  • MRP disrupted the MITA-TBK1 interaction, inhibiting the TBK1-IRF3 axis, but still allowed NF-κB activation via iκB kinase interaction.

Conclusions:

  • MRP functions as a dominant-negative regulator of MITA-mediated type I interferon production.
  • MRP exhibits differential regulation of innate immune pathways depending on the stimulus, notably inhibiting IFN induction while allowing NF-κB activation.
  • The distinct functions of MRP highlight the complexity of immune regulation through alternative splicing of adaptor proteins.

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