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.

Cancer Cell Biology Programme Centro Nacional de Investigaciones Oncológicas CNIO Madrid Spain

Department of Cellular and Molecular Pharmacology University of California San Francisco San Francisco CA USA

Department of Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai New York NY USA

Department of Medicine Clinical Immunology Icahn School of Medicine at Mount Sinai New York NY USA

Department of Medicine Northwestern University Feinberg School of Medicine Chicago IL USA

Department of Microbiology Icahn School of Medicine at Mount Sinai New York NY USA

Department of Obstetrics and Gynecology Stanford University Stanford CA USA

Department of Pathology Icahn School of Medicine at Mount Sinai New York NY USA

Department of Psychiatry Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York NY USA

Division of Hematology and Oncology Department of Medicine Icahn School of Medicine at Mount Sinai New York NY USA

Division of Infectious Diseases Department of Medicine Icahn School of Medicine at Mount Sinai New York NY USA

Epinova Epigenetics Discovery Performance Unit Immuno Inflammation Therapy Area GlaxoSmithKline Medicines Research Centre Stevenage UK

Global Health and Emerging Pathogens Institute Icahn School of Medicine at Mount Sinai New York NY USA

Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai New York NY USA

Influenza Division National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention Atlanta GA USA

Institute for Stem Cell Biology and Regenerative Medicine Stanford University Stanford CA USA

Institute of Molecular and Cell Biology Singapore Singapore

Laboratory of Immune Cell Epigenetics and Signaling The Rockefeller University New York NY USA

Life Science Research Centre Faculty of Science University of Ostrava Ostrava Czech Republic

Mount Sinai Center for Therapeutics Discovery Departments of Pharmacological Sciences and Oncological Sciences Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY USA

Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY USA

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