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MERS-CoV antagonizes PKR activation by inhibiting its condensation at viral replication complexes

Ebba K Blomqvist1,2,3, Nicole Bracci4,5, Helena Winstone4,5

  • 1Department of Molecular Medicine, The Herbert Wertheim University of Florida Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, USA.

Biorxiv : the Preprint Server for Biology
|September 2, 2025
PubMed

Insights

Middle East respiratory syndrome coronavirus (MERS-CoV) antagonizes the protein kinase R (PKR) pathway. MERS-CoV NS4a protein prevents PKR activation by blocking PKR condensation on viral dsRNA, a crucial step for innate immunity.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Middle East respiratory syndrome coronavirus (MERS-CoV) is a pathogenic virus that suppresses innate immune responses.
  • The protein kinase R (PKR) pathway is a key component of the innate immune system targeted by MERS-CoV.

Purpose of the Study:

  • To investigate the mechanism of PKR activation in response to MERS-CoV.
  • To elucidate how MERS-CoV antagonizes the PKR pathway.

Main Methods:

  • Utilized an immunostimulatory MERS-CoV mutant with an inactive endoribonuclease U and a deletion of accessory protein NS4a.
  • Observed PKR condensation and activation on viral dsRNA associated with double-membrane vesicles (DMVs).
  • Examined the role of MERS-CoV NS4a protein in PKR inhibition.

Main Results:

  • PKR activates by condensing on viral dsRNA near DMVs, then dissociates to phosphorylate eIF2α.
  • MERS-CoV NS4a protein inhibits PKR activation by binding to dsRNA and preventing PKR condensation.
  • PKR condensation and activation were also observed in response to Zika virus.

Conclusions:

  • PKR activation involves condensation on viral dsRNA at replication complexes, followed by autophosphorylation and cytosolic relocalization.
  • MERS-CoV NS4a antagonizes this antiviral pathway by inhibiting PKR condensation.
  • This study provides a model for PKR activation by positive-strand RNA viruses and MERS-CoV's immune evasion strategy.
Keywords:
MERS-CoVNS4aPKRZika viruscondensationdsRNAinnate immunitynsp15viral antagonist proteins

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