Influenza virus infection causes global RNAPII termination defects

Nan Zhao; Vittorio Sebastiano; Natasha Moshkina; Nacho Mena; Judd Hultquist; David Jimenez-Morales; Yixuan Ma; Alex Rialdi; Randy Albrecht; Romain Fenouil; Maria Teresa Sánchez-Aparicio; Juan Ayllon; Sweta Ravisankar; Bahareh Haddad; Jessica Sook Yuin Ho; Diana Low; Jian Jin; Vyacheslav Yurchenko; Rab K. Prinjha; Alexander Tarakhovsky; Massimo Squatrito; Dalila Pinto; Kimaada Allette; Minji Byun; Melissa Laird Smith; Robert Sebra; Ernesto Guccione; Terrence Tumpey; Nevan Krogan; Benjamin Greenbaum; Harm van Bakel; Adolfo García-Sastre; Ivan Marazzi

doi:10.1038/s41594-018-0124-7

Influenza virus infection causes global RNAPII termination defects

Nan Zhao, Vittorio Sebastiano, Natasha Moshkina, Nacho Mena, Judd Hultquist, David Jimenez-Morales, Yixuan Ma, Alex Rialdi, Randy Albrecht, Romain Fenouil, Maria Teresa Sánchez-Aparicio, Juan Ayllon, Sweta Ravisankar, Bahareh Haddad, Jessica Sook Yuin Ho, Diana Low, Jian Jin, Vyacheslav Yurchenko, Rab K. Prinjha, Alexander TarakhovskyMassimo Squatrito, Dalila Pinto, Kimaada Allette, Minji Byun, Melissa Laird Smith, Robert Sebra, Ernesto Guccione, Terrence Tumpey, Nevan Krogan, Benjamin Greenbaum, Harm van Bakel, Adolfo García-Sastre, Ivan Marazzi^*

^*Corresponding author for this work

Medicine, Infectious Diseases Division

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

Abstract

Viral infection perturbs host cells and can be used to uncover regulatory mechanisms controlling cellular responses and susceptibility to infections. Using cell biological, biochemical, and genetic tools, we reveal that influenza A virus (IAV) infection induces global transcriptional defects at the 3′ ends of active host genes and RNA polymerase II (RNAPII) run-through into extragenic regions. Deregulated RNAPII leads to expression of aberrant RNAs (3′ extensions and host-gene fusions) that ultimately cause global transcriptional downregulation of physiological transcripts, an effect influencing antiviral response and virulence. This phenomenon occurs with multiple strains of IAV, is dependent on influenza NS1 protein, and can be modulated by SUMOylation of an intrinsically disordered region (IDR) of NS1 expressed by the 1918 pandemic IAV strain. Our data identify a strategy used by IAV to suppress host gene expression and indicate that polymorphisms in IDRs of viral proteins can affect the outcome of an infection.

Original language	English (US)
Pages (from-to)	885-893
Number of pages	9
Journal	Nature Structural and Molecular Biology
Volume	25
Issue number	9
DOIs	https://doi.org/10.1038/s41594-018-0124-7
State	Published - Sep 1 2018

Funding

We thank all members of the laboratories of I.M. and A.G.-S., and J. Bloom and A. Kornblihtt for valuable discussions and suggestions on the manuscript. We thank the Medicinal Chemistry Core, Integrated Screening Core, Microscopy CoRE,, and Global Health and Emerging Pathogens Institute (GHEPI) at the Icahn School of Medicine at Mount Sinai. H.v.B., I.M., and A.G.-S. are partially supported by HHSN272201400008C– Center for Research on Influenza Pathogenesis (CRIP), a NIAID-funded Center of Excellence for Influenza Research and Surveillance (CEIRS). I.M. is supported in part by the Department of Defense W911NF-14-1-0353. I.M. and H.v.B. are supported by NIH grant 1R01AN3663134. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai.

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Structural Biology
Molecular Biology

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Zhao, N., Sebastiano, V., Moshkina, N., Mena, N., Hultquist, J., Jimenez-Morales, D., Ma, Y., Rialdi, A., Albrecht, R., Fenouil, R., Sánchez-Aparicio, M. T., Ayllon, J., Ravisankar, S., Haddad, B., Ho, J. S. Y., Low, D., Jin, J., Yurchenko, V., Prinjha, R. K., ... Marazzi, I. (2018). Influenza virus infection causes global RNAPII termination defects. Nature Structural and Molecular Biology, 25(9), 885-893. https://doi.org/10.1038/s41594-018-0124-7

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abstract = "Viral infection perturbs host cells and can be used to uncover regulatory mechanisms controlling cellular responses and susceptibility to infections. Using cell biological, biochemical, and genetic tools, we reveal that influenza A virus (IAV) infection induces global transcriptional defects at the 3′ ends of active host genes and RNA polymerase II (RNAPII) run-through into extragenic regions. Deregulated RNAPII leads to expression of aberrant RNAs (3′ extensions and host-gene fusions) that ultimately cause global transcriptional downregulation of physiological transcripts, an effect influencing antiviral response and virulence. This phenomenon occurs with multiple strains of IAV, is dependent on influenza NS1 protein, and can be modulated by SUMOylation of an intrinsically disordered region (IDR) of NS1 expressed by the 1918 pandemic IAV strain. Our data identify a strategy used by IAV to suppress host gene expression and indicate that polymorphisms in IDRs of viral proteins can affect the outcome of an infection.",

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Zhao, N, Sebastiano, V, Moshkina, N, Mena, N, Hultquist, J, Jimenez-Morales, D, Ma, Y, Rialdi, A, Albrecht, R, Fenouil, R, Sánchez-Aparicio, MT, Ayllon, J, Ravisankar, S, Haddad, B, Ho, JSY, Low, D, Jin, J, Yurchenko, V, Prinjha, RK, Tarakhovsky, A, Squatrito, M, Pinto, D, Allette, K, Byun, M, Smith, ML, Sebra, R, Guccione, E, Tumpey, T, Krogan, N, Greenbaum, B, van Bakel, H, García-Sastre, A & Marazzi, I 2018, 'Influenza virus infection causes global RNAPII termination defects', Nature Structural and Molecular Biology, vol. 25, no. 9, pp. 885-893. https://doi.org/10.1038/s41594-018-0124-7

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AU - Zhao, Nan

AU - Sebastiano, Vittorio

AU - Moshkina, Natasha

AU - Mena, Nacho

AU - Hultquist, Judd

AU - Jimenez-Morales, David

AU - Ma, Yixuan

AU - Rialdi, Alex

AU - Albrecht, Randy

AU - Fenouil, Romain

AU - Sánchez-Aparicio, Maria Teresa

AU - Ayllon, Juan

AU - Ravisankar, Sweta

AU - Haddad, Bahareh

AU - Ho, Jessica Sook Yuin

AU - Low, Diana

AU - Jin, Jian

AU - Yurchenko, Vyacheslav

AU - Prinjha, Rab K.

AU - Tarakhovsky, Alexander

AU - Squatrito, Massimo

AU - Pinto, Dalila

AU - Allette, Kimaada

AU - Byun, Minji

AU - Smith, Melissa Laird

AU - Sebra, Robert

AU - Guccione, Ernesto

AU - Tumpey, Terrence

AU - Krogan, Nevan

AU - Greenbaum, Benjamin

AU - van Bakel, Harm

AU - García-Sastre, Adolfo

AU - Marazzi, Ivan

PY - 2018/9/1

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N2 - Viral infection perturbs host cells and can be used to uncover regulatory mechanisms controlling cellular responses and susceptibility to infections. Using cell biological, biochemical, and genetic tools, we reveal that influenza A virus (IAV) infection induces global transcriptional defects at the 3′ ends of active host genes and RNA polymerase II (RNAPII) run-through into extragenic regions. Deregulated RNAPII leads to expression of aberrant RNAs (3′ extensions and host-gene fusions) that ultimately cause global transcriptional downregulation of physiological transcripts, an effect influencing antiviral response and virulence. This phenomenon occurs with multiple strains of IAV, is dependent on influenza NS1 protein, and can be modulated by SUMOylation of an intrinsically disordered region (IDR) of NS1 expressed by the 1918 pandemic IAV strain. Our data identify a strategy used by IAV to suppress host gene expression and indicate that polymorphisms in IDRs of viral proteins can affect the outcome of an infection.

AB - Viral infection perturbs host cells and can be used to uncover regulatory mechanisms controlling cellular responses and susceptibility to infections. Using cell biological, biochemical, and genetic tools, we reveal that influenza A virus (IAV) infection induces global transcriptional defects at the 3′ ends of active host genes and RNA polymerase II (RNAPII) run-through into extragenic regions. Deregulated RNAPII leads to expression of aberrant RNAs (3′ extensions and host-gene fusions) that ultimately cause global transcriptional downregulation of physiological transcripts, an effect influencing antiviral response and virulence. This phenomenon occurs with multiple strains of IAV, is dependent on influenza NS1 protein, and can be modulated by SUMOylation of an intrinsically disordered region (IDR) of NS1 expressed by the 1918 pandemic IAV strain. Our data identify a strategy used by IAV to suppress host gene expression and indicate that polymorphisms in IDRs of viral proteins can affect the outcome of an infection.

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Influenza virus infection causes global RNAPII termination defects

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