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mRNA 3’UTR lengthening by alternative polyadenylation attenuates inflammatory responses and correlates with virulence of Influenza A virus

Author

Listed:
  • Valter Bergant

    (TUM School of Medicine, Technical University of Munich
    Max Planck Institute of Biochemistry)

  • Daniel Schnepf

    (Medical Center University of Freiburg
    The Francis Crick Institute)

  • Niklas Andrade Krätzig

    (Technical University of Munich
    Technical University of Munich)

  • Philipp Hubel

    (Max Planck Institute of Biochemistry)

  • Christian Urban

    (TUM School of Medicine, Technical University of Munich
    Max Planck Institute of Biochemistry)

  • Thomas Engleitner

    (Technical University of Munich
    Technical University of Munich)

  • Ronald Dijkman

    (University of Bern
    Institute of Virology and Immunology
    University of Bern)

  • Bernhard Ryffel

    (CNRS
    University of Orléans)

  • Katja Steiger

    (Technical University of Munich)

  • Percy A. Knolle

    (Technical University of Munich)

  • Georg Kochs

    (Medical Center University of Freiburg
    University of Freiburg)

  • Roland Rad

    (Technical University of Munich
    Technical University of Munich
    Technical University of Munich)

  • Peter Staeheli

    (Medical Center University of Freiburg)

  • Andreas Pichlmair

    (TUM School of Medicine, Technical University of Munich
    Max Planck Institute of Biochemistry
    Munich Partner Site)

Abstract

Changes of mRNA 3’UTRs by alternative polyadenylation (APA) have been associated to numerous pathologies, but the mechanisms and consequences often remain enigmatic. By combining transcriptomics, proteomics and recombinant viruses we show that all tested strains of IAV, including A/PR/8/34(H1N1) (PR8) and A/Cal/07/2009 (H1N1) (Cal09), cause APA. We mapped the effect to the highly conserved glycine residue at position 184 (G184) of the viral non-structural protein 1 (NS1). Unbiased mass spectrometry-based analyses indicate that NS1 causes APA by perturbing the function of CPSF4 and that this function is unrelated to virus-induced transcriptional shutoff. Accordingly, IAV strain PR8, expressing an NS1 variant with weak CPSF binding, does not induce host shutoff but only APA. However, recombinant IAV (PR8) expressing NS1(G184R) lacks binding to CPSF4 and thereby also the ability to cause APA. Functionally, the impaired ability to induce APA leads to an increased inflammatory cytokine production and an attenuated phenotype in a mouse infection model. Investigating diverse viral infection models showed that APA induction is a frequent ability of many pathogens. Collectively, we propose that targeting of the CPSF complex, leading to widespread alternative polyadenylation of host transcripts, constitutes a general immunevasion mechanism employed by a variety of pathogenic viruses.

Suggested Citation

  • Valter Bergant & Daniel Schnepf & Niklas Andrade Krätzig & Philipp Hubel & Christian Urban & Thomas Engleitner & Ronald Dijkman & Bernhard Ryffel & Katja Steiger & Percy A. Knolle & Georg Kochs & Rola, 2023. "mRNA 3’UTR lengthening by alternative polyadenylation attenuates inflammatory responses and correlates with virulence of Influenza A virus," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40469-6
    DOI: 10.1038/s41467-023-40469-6
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    References listed on IDEAS

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