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PACT Facilitates RNA-Induced Activation of MDA5 by Promoting MDA5 Oligomerization

Pak-Yin Lui1,2, Lok-Yin Roy Wong1,2, Ting-Hin Ho1,2

  • 1School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.

Journal of Immunology (Baltimore, Md. : 1950)
|August 2, 2017
PubMed

Insights

PACT protein acts as a crucial coactivator for MDA5 (a sensor of viral RNA), enhancing the innate immune response. It facilitates MDA5

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • MDA5 is a key sensor of double-stranded RNA (dsRNA) and RNA viruses, initiating the type I interferon (IFN) signaling cascade for innate antiviral defense.
  • MDA5's low affinity for dsRNA necessitates cellular coactivators for optimal antiviral activity.

Purpose of the Study:

  • To identify and characterize the function of cellular coactivators involved in MDA5-mediated antiviral signaling.
  • To elucidate the role of dsRNA-binding protein PACT in the MDA5-dependent type I IFN response.

Main Methods:

  • Utilized PACT-knockout and PACT-knockdown cellular models to assess MDA5 activation.
  • Investigated the effect of PACT overexpression on MDA5-mediated IFN production.
  • Analyzed PACT's interaction with dsRNA, MDA5 oligomerization, and MDA5 recruitment to dsRNA.

Main Results:

  • PACT deficiency severely impaired virus- and poly(I:C)-induced MDA5 activation, while PACT overexpression potentiated it.
  • PACT specifically augmented IRF3-dependent type I IFN production, without affecting MDA5-mediated NF-κB activation.
  • PACT's function required dsRNA interaction, promoting MDA5 oligomerization and recruitment to dsRNA.

Conclusions:

  • PACT is an essential coactivator for MDA5, facilitating dsRNA-induced MDA5 oligomerization and type I IFN production.
  • PACT also acts as a coactivator for RIG-I, highlighting its broad role in innate antiviral immunity.
  • PACT enhances the innate immune system's ability to detect and respond to viral RNA.

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