title: 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.
authors.affiliation: Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA. imarazzi@rockefeller.edu
authors.forename: Ivan
authors.initials: I
authors.lastname: Marazzi
authors.forename: Jessica S Y
authors.initials: JS
authors.lastname: Ho
authors.forename: Jaehoon
authors.initials: J
authors.lastname: Kim
authors.forename: Balaji
authors.initials: B
authors.lastname: Manicassamy
authors.forename: Scott
authors.initials: S
authors.lastname: Dewell
authors.forename: Randy A
authors.initials: RA
authors.lastname: Albrecht
authors.forename: Chris W
authors.initials: CW
authors.lastname: Seibert
authors.forename: Uwe
authors.initials: U
authors.lastname: Schaefer
authors.forename: Kate L
authors.initials: KL
authors.lastname: Jeffrey
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.forename: Kevin
authors.initials: K
authors.lastname: Lee
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roeder
authors.forename: Alexander
authors.initials: A
authors.lastname: Tarakhovsky
mesh_terms: D000595:Amino Acid Sequence; D005786:Gene Expression Regulation / Q000276:immunology; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D007251:Influenza, Human / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000821:virology; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D006657:Histones; C085820:INS1 protein, influenza virus; D009687:Nuclear Proteins; C501972:PAF1 protein, human; D014157:Transcription Factors; D017361:Viral Nonstructural Proteins