Suppression of the antiviral response by an influenza histone mimic

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. Access through your institution Buy or subscribe This is a preview of subscription

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REGULATION VIA HISTONE MIMICRY Article 05 October 2022 NEIL1 BLOCK IFN-Β PRODUCTION AND ENHANCE VRNP FUNCTION TO FACILITATE INFLUENZA A VIRUS PROLIFERATION Article Open access 21 November

2024 THE INFLUENZA VIRUS PB2 PROTEIN EVADES ANTIVIRAL INNATE IMMUNITY BY INHIBITING JAK1/STAT SIGNALLING Article Open access 21 October 2022 REFERENCES * Kornberg, R. D. & Thomas, J. O.

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326, 729–733 (2009) Article  ADS  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank P. deGross and A. Rudensky for the mass spectroscopy analysis of the NS1 binding

proteins. A. Rojas Soto, D. Reinberg, M. Dobenecker and T. Zhanyun provided us with recombinant CHD1 (A.R.S., D.R.), recombinant Set7/9 (M.D.) and Set1C (T.Z.). F. Casadio, P. Lewis, O.

Binda, O. Gozani, N. Levenkova, A. Mele, R. Darnell, L. Core, J. Lis and P. Palese gave us valuable technical advice and help with data analysis. We acknowledge the Rockefeller University

Genomics Resource Center for technical support. We thank R. Cadagan, A. Santana, W. Huang, R. Chandramouli and H. Zebronsky for technical assistance, R. Rizzo for help with manuscript

preparation and C. Nathan for discussion. L.M.K. for artwork. B.M is supported by NIH/NIAID K99 Pathway to Independence award (1K99AI095320-01). A.G.-S. is partially supported by NIAID

grants R01AI046954, U19AI083025 and by CRIP (Center for Research in Influenza Pathogenesis), an NIAID funded Center of Excellence for Influenza Research and Surveillance, HHSN266200700010C.

R.G.R. is supported by NIH grant CA129325. J.K. is supported by Charles H. Revson Foundation. I.M. is supported by American Italian Cancer Foundation. J.H. is supported by the Agency for

Science, Technology and Research (A*STAR), Singapore. A.T. is supported by the NIH grant R01AI068058 and by Starr Cancer Consortium. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Laboratory

of Immune Cell Epigenetics and Signaling, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA, Ivan Marazzi, Jessica S. Y. Ho, Uwe Schaefer, Kate L. Jeffrey & 

Alexander Tarakhovsky * Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA, Jaehoon Kim & Robert G. Roeder *

Department of Microbiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA, Balaji Manicassamy, Randy A. Albrecht, Chris W. Seibert & 

Adolfo García-Sastre * Global Health and Infectious Pathogens Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA, Balaji

Manicassamy, Randy A. Albrecht & Adolfo García-Sastre * Genomics Resource Center, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA, Scott Dewell * Epinova DPU,

Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK, Rab K. Prinjha & Kevin Lee *

Department of Medicine, Division of Infectious Diseases, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA, Adolfo García-Sastre Authors *

Ivan Marazzi View author publications You can also search for this author inPubMed Google Scholar * Jessica S. Y. Ho View author publications You can also search for this author inPubMed 

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author inPubMed Google Scholar * Scott Dewell View author publications You can also search for this author inPubMed Google Scholar * Randy A. Albrecht View author publications You can also

search for this author inPubMed Google Scholar * Chris W. Seibert View author publications You can also search for this author inPubMed Google Scholar * Uwe Schaefer View author publications

You can also search for this author inPubMed Google Scholar * Kate L. Jeffrey View author publications You can also search for this author inPubMed Google Scholar * Rab K. Prinjha View

author publications You can also search for this author inPubMed Google Scholar * Kevin Lee View author publications You can also search for this author inPubMed Google Scholar * Adolfo

García-Sastre View author publications You can also search for this author inPubMed Google Scholar * Robert G. Roeder View author publications You can also search for this author inPubMed 

Google Scholar * Alexander Tarakhovsky View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS I.M. contributed to design, execution, analysis of

the experiments and manuscript preparation. J.S.Y.H. studied the role of PAF1 in viral infection and assisted in manuscript preparation. J.K. and R.R. studied the impact of NS1 on hPAF1C and

transcriptional elongation. B.M., R.A.A. engineered the recombinant influenza viruses and studied viral infectivity. U.S. was involved in gene expression studies. S.D. performed

bioinformatic analysis. C.W.S. generated antibody against viral polymerase. K.L.J. gave technical assistance. R.K.P. and K.L. contributed to manuscript preparation and enabled ChIP-seq and

RNA-seq. A.G.-S. supervised and discussed the work with infectious influenza viruses. A.T. conceived and supervised this study and wrote the final manuscript. CORRESPONDING AUTHORS

Correspondence to Ivan Marazzi or Alexander Tarakhovsky. ETHICS DECLARATIONS COMPETING INTERESTS R.K.P. and K.L. are employees of GlaxoSmithKline. Research support, excluding salaries to the

members of The Rockefeller University, was partially provided by GlaxoSmithKline. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION This file contains Supplementary Figures 1-12,

Supplementary Methods, additional references and full legends for Supplementary Tables 1-8. (PDF 1437 kb) SUPPLEMENTARY TABLE 1 This table shows genes affected by Influenza Infection - see

Supplementary Information file for full legend. (XLS 135 kb) SUPPLEMENTARY TABLE 2 This table contains a list of genes used for the integrated ChIP-seq profile - see Supplementary

Information file for full legend. (XLS 43 kb) SUPPLEMENTARY TABLE 3 This table shows siPAF dependent genes in PR8/∆NS1 infected cells - see Supplementary Information file for full legend.

(XLS 249 kb) SUPPLEMENTARY TABLE 4 This table shows siPAF dependent genes in Influenza (H1N1) infected cells - see Supplementary Information file for full legend. (XLS 656 kb) SUPPLEMENTARY

TABLE 5 This table shows siPAF dependent genes in Influenza (H1N1) infected cells - see Supplementary Information file for full legend. (XLS 596 kb) SUPPLEMENTARY TABLE 6 This table shows

siPAF dependent genes in Poly(I:C) transfected cells - see Supplementary Information file for full legend. (XLS 888 kb) SUPPLEMENTARY TABLE 7 This table shows siPAF dependent genes in IFNβ1

treated cells - see Supplementary Information file for full legend. (XLS 111 kb) SUPPLEMENTARY TABLE 8 This table shows that expression of housekeeping genes are not affected by siPAF

mediated hPAF1 deficiency - see Supplementary Information file for full legend. (XLS 24 kb) POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR

FIG. 3 POWERPOINT SLIDE FOR FIG. 4 POWERPOINT SLIDE FOR FIG. 5 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Marazzi, I., Ho, J., Kim, J. _et al._

Suppression of the antiviral response by an influenza histone mimic. _Nature_ 483, 428–433 (2012). https://doi.org/10.1038/nature10892 Download citation * Received: 07 September 2011 *

Accepted: 23 January 2012 * Published: 14 March 2012 * Issue Date: 22 March 2012 * DOI: https://doi.org/10.1038/nature10892 SHARE THIS ARTICLE Anyone you share the following link with will

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