title: Zika Virus Targets Human STAT2 to Inhibit Type I Interferon Signaling.
abstract: The ongoing epidemic of Zika virus (ZIKV) illustrates the importance of flaviviruses as emerging human pathogens. All vector-borne flaviviruses studied thus far have to overcome type I interferon (IFN) to replicate and cause disease in vertebrates. The mechanism(s) by which ZIKV antagonizes IFN signaling is unknown. Here, we report that the nonstructural protein NS5 of ZIKV and other flaviviruses examined could suppress IFN signaling, but through different mechanisms. ZIKV NS5 expression resulted in proteasomal degradation of the IFN-regulated transcriptional activator STAT2 from humans, but not mice, which may explain the requirement for IFN deficiency to observe ZIKV-induced disease in mice. The mechanism of ZIKV NS5 resembles dengue virus (DENV) NS5 and not its closer relative, Spondweni virus (SPOV). However, unlike DENV, ZIKV did not require the E3 ubiquitin ligase UBR4 to induce STAT2 degradation. Hence, flavivirus NS5 proteins exhibit a remarkable functional convergence in IFN antagonism, albeit by virus-specific mechanisms.
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: Alesha
authors.initials: A
authors.lastname: Grant
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA.
authors.forename: Sanket S
authors.initials: SS
authors.lastname: Ponia
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: Shashank
authors.initials: S
authors.lastname: Tripathi
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: Vinod
authors.initials: V
authors.lastname: Balasubramaniam
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.
authors.forename: Marion
authors.initials: M
authors.lastname: Sourisseau
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Megan C
authors.initials: MC
authors.lastname: Schwarz
authors.affiliation: Laboratory of Arbovirus and Imported Viral Diseases, National Center of Microbiology, Institute of Health Carlos III, 28029 Madrid, Spain.
authors.forename: Mari Paz
authors.initials: MP
authors.lastname: Sánchez-Seco
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Evans
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA.
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Best
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, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: adolfo.garcia-sastre@mssm.edu.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
mesh_terms: D000818:Animals; D001483:Base Sequence; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D007370:Interferon Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D010802:Phylogeny; D050795:STAT2 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D000071244:Zika Virus / Q000378:metabolism*; D000071243:Zika Virus Infection / Q000378:metabolism* / Q000821:virology
chemical_list: D002148:Calmodulin-Binding Proteins; D003598:Cytoskeletal Proteins; D007370:Interferon Type I; C096041:NS5 protein, flavivirus; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; C494085:Stat2 protein, mouse; D017361:Viral Nonstructural Proteins; C505833:UBR4 protein, human; D044767:Ubiquitin-Protein Ligases