TY - JOUR
T1 - Influenza virus infection causes global RNAPII termination defects
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
N1 - Funding Information:
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.
PY - 2018/9/1
Y1 - 2018/9/1
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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U2 - 10.1038/s41594-018-0124-7
DO - 10.1038/s41594-018-0124-7
M3 - Article
C2 - 30177761
AN - SCOPUS:85053010233
VL - 25
SP - 885
EP - 893
JO - Nature Structural Biology
JF - Nature Structural Biology
SN - 1545-9993
IS - 9
ER -