Suppression of the antiviral response by an influenza histone mimic

Ivan Marazzi (), Jessica S. Y. Ho, Jaehoon Kim, Balaji Manicassamy, Scott Dewell, Randy A. Albrecht, Chris W. Seibert, Uwe Schaefer, Kate L. Jeffrey, Rab K. Prinjha, Kevin Lee, Adolfo García-Sastre, Robert G. Roeder and Alexander Tarakhovsky ()
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Ivan Marazzi: Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
Jessica S. Y. Ho: Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
Jaehoon Kim: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
Balaji Manicassamy: Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA
Scott Dewell: Genomics Resource Center, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
Randy A. Albrecht: Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA
Chris W. Seibert: Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA
Uwe Schaefer: Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
Kate L. Jeffrey: Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
Rab K. Prinjha: Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Kevin Lee: Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Adolfo García-Sastre: Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA
Robert G. Roeder: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
Alexander Tarakhovsky: Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA

Nature, 2012, vol. 483, issue 7390, 428-433

Abstract: Abstract Viral infection is commonly associated with virus-driven hijacking of host proteins. Here we describe a novel mechanism by which influenza virus affects host cells through the interaction of influenza non-structural protein 1 (NS1) with the infected cell epigenome. We show that the NS1 protein of influenza A H3N2 subtype possesses a histone-like sequence (histone mimic) that is used by the virus to target the human PAF1 transcription elongation complex (hPAF1C). We demonstrate that binding of NS1 to hPAF1C depends on the NS1 histone mimic and results in suppression of hPAF1C-mediated transcriptional elongation. Furthermore, human PAF1 has a crucial role in the antiviral response. Loss of hPAF1C binding by NS1 attenuates influenza infection, whereas hPAF1C deficiency reduces antiviral gene expression and renders cells more susceptible to viruses. We propose that the histone mimic in NS1 enables the influenza virus to affect inducible gene expression selectively, thus contributing to suppression of the antiviral response.

Date: 2012
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DOI: 10.1038/nature10892

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