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PKR engages viral RNA and intron-retained host transcripts during poxvirus infection

Ruilin Zhang1, Xiang Ye1, Andrew C Dixson2

  • 1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Vanderbilt Center for Immunobiology, and Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN 37232-2363, USA.

Cell Reports
|August 8, 2026
PubMed

Insights

Protein kinase R (PKR) detects viral RNA and host RNAs with retained introns during vaccinia virus infection. Defective RNA processing activates PKR, crucial for innate antiviral defense.

Area of Science:

  • Immunology
  • Virology
  • Molecular Biology

Background:

  • Double-stranded RNA (dsRNA) recognition is key to antiviral immunity.
  • Mechanisms of RNA sensor activation during viral infections are not fully understood.

Purpose of the Study:

  • To investigate the activation of Protein Kinase R (PKR) during vaccinia virus (VacV) infection.
  • To identify the RNA species that activate PKR and the factors modulating its response.

Main Methods:

  • Analysis of PKR binding to viral and host RNAs during VacV infection.
  • Investigating the role of RNase L in pre-mRNA splicing and subsequent PKR activation.
  • Utilizing small-molecule inhibitors to probe splicing-dependent PKR activation.
  • Examining the influence of PACT and viral E3 on PKR signaling.

Main Results:

  • PKR preferentially binds to viral RNAs and host intron-retaining transcripts during VacV infection.
  • RNase L activation impairs pre-mRNA splicing, leading to cytoplasmic accumulation of intron-retaining RNAs.
  • Splicing inhibition activates PKR independently of RNase L, indicating defective splicing as a PKR ligand source.
  • PKR also interacts with structured viral RNAs, and its signaling is modulated by PACT and viral E3.

Conclusions:

  • PKR acts as a sensor for both viral and aberrant host RNAs during infection.
  • Defective RNA processing, including splicing errors, contributes to PKR activation.
  • PKR integrates signals from RNA processing, viral replication, and innate immunity.
Keywords:
CP: immunologyCP: molecular biologyOASPKRRNase Lantiviral immunitydsRNApoxvirusvaccinia virus

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