title: The interferon signaling antagonist function of yellow fever virus NS5 protein is activated by type I interferon.
abstract: To successfully establish infection, flaviviruses have to overcome the antiviral state induced by type I interferon (IFN-I). The nonstructural NS5 proteins of several flaviviruses antagonize IFN-I signaling. Here we show that yellow fever virus (YFV) inhibits IFN-I signaling through a unique mechanism that involves binding of YFV NS5 to the IFN-activated transcription factor STAT2 only in cells that have been stimulated with IFN-I. This NS5-STAT2 interaction requires IFN-I-induced tyrosine phosphorylation of STAT1 and the K63-linked polyubiquitination at a lysine in the N-terminal region of YFV NS5. We identified TRIM23 as the E3 ligase that interacts with and polyubiquitinates YFV NS5 to promote its binding to STAT2 and trigger IFN-I signaling inhibition. Our results demonstrate the importance of YFV NS5 in overcoming the antiviral action of IFN-I and offer a unique example of a viral protein that is activated by the same host pathway that it inhibits.
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.
authors.forename: Maudry
authors.initials: M
authors.lastname: Laurent-Rolle
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.
authors.forename: Juliet
authors.initials: J
authors.lastname: Morrison
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rajsbaum
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.
authors.forename: Jesica M Levingston
authors.initials: JML
authors.lastname: Macleod
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.|Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Via F Delpino 1, 80137 Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pisanelli
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.
authors.forename: Alissa
authors.initials: A
authors.lastname: Pham
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Ayllon
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Miorin
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.
authors.forename: Carles
authors.initials: C
authors.lastname: Martinez
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: tenOever
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. USA.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002460:Cell Line; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D050794:STAT1 Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015004:Yellow Fever / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D015005:Yellow fever virus / Q000235:genetics / Q000378:metabolism*
chemical_list: C096041:NS5 protein, flavivirus; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C080681:TRIM23 protein, human; D017361:Viral Nonstructural Proteins; D016899:Interferon-beta; D019204:GTP-Binding Proteins