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Journal of General Virology header logo Journal of General Virology

Volume 106, Issue 3

The Cap-proximal secondary structures of the 5′UTRs of parainfluenza virus 5 mRNAs specify differential sensitivity to type I interferon and IFIT1 Open Access

Abstract

Parainfluenza virus 5 (PIV5) is a paramyxovirus that has been isolated from numerous mammalian hosts and is notable for its ability to cause persistent infections. Although PIV5-infected cells are resistant to IFN due to the ability of the V protein to target STAT1 for degradation, PIV5 shows residual IFN sensitivity when infecting cells that have already been exposed to IFN. We have previously reported that the human IFN-stimulated gene with the greatest inhibitory effect on PIV5 is IFIT1. IFIT1 inhibits the translation of incompletely methylated mRNAs (Cap0) but not those 2′-O-methylated at the first transcribed nucleotide (Cap1). All are thought to generate Cap1 mRNA, so the sensitivity of PIV5 to IFIT1 is surprising. Here, we show that PIV5 generates Cap0 mRNA but not Cap1 mRNA, thus explaining its sensitivity to IFIT1. Furthermore, the sensitivity of different PIV5 genes to IFIT1-mediated translation inhibition varies. In the absence of complete Cap methylation, we show that the presence or absence of 5′-terminal RNA hairpin structures in the 5′UTRs of PIV5 genes determines the extent to which they are sensitive to IFIT1. Notably, the genes involved in RNA synthesis are relatively resistant to IFIT1 inhibition. This presents a potential mechanism by which IFIT1 can regulate the outcome of PIV5 infection in response to IFN and may be important in allowing the virus to establish prolonged/persistent infections.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): IFIT1 , IFN , mRNA Cap structure and parainfluenza virus 5 (PIV5)
Funding
This study was supported by the:
  • St George's, University of London
    • Principal Award Recipient: JacquelineHankinson
  • Cancer Research UK Cancer Imaging Centre (Award CTRQQR-2021\100006)
    • Principal Award Recipient: VictoriaH Cowling
  • Cancer Research UK (Award A17196/A31287)
    • Principal Award Recipient: VictoriaH Cowling
  • Wellcome Trust (Award 101792/Z/13/Z)
    • Principal Award Recipient: RichardRandall
  • Wellcome Trust (Award 101788/Z/13/Z)
    • Principal Award Recipient: SteveGoodbourn
© 2025 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2025-03-27
2025-12-13

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The Cap-proximal secondary structures of the 5′UTRs of parainfluenza virus 5 mRNAs specify differential sensitivity to type I interferon and IFIT1
J. Gen. Virol. 106, 002093 (2025); https://doi.org/10.1099/jgv.0.002093
/content/journal/jgv/10.1099/jgv.0.002093
/content/journal/jgv/10.1099/jgv.0.002093
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