title: Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1.
abstract: During antiviral defense, interferon (IFN) signaling triggers nuclear transport of tyrosine-phosphorylated STAT1 (PY-STAT1), which occurs via a subset of karyopherin alpha (KPNA) nuclear transporters. Many viruses, including Ebola virus, actively antagonize STAT1 signaling to counteract the antiviral effects of IFN. Ebola virus VP24 protein (eVP24) binds KPNA to inhibit PY-STAT1 nuclear transport and render cells refractory to IFNs. We describe the structure of human KPNA5 C terminus in complex with eVP24. In the complex, eVP24 recognizes a unique nonclassical nuclear localization signal (NLS) binding site on KPNA5 that is necessary for efficient PY-STAT1 nuclear transport. eVP24 binds KPNA5 with very high affinity to effectively compete with and inhibit PY-STAT1 nuclear transport. In contrast, eVP24 binding does not affect the transport of classical NLS cargo. Thus, eVP24 counters cell-intrinsic innate immunity by selectively targeting PY-STAT1 nuclear import while leaving the transport of other cargo that may be required for viral replication unaffected.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Megan R
authors.initials: MR
authors.lastname: Edwards
authors.affiliation: Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Dominika M
authors.initials: DM
authors.lastname: Borek
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Feagins
authors.affiliation: Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University, St. Louis, MO 63110, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Mittal
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Alinger
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Kayla N
authors.initials: KN
authors.lastname: Berry
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Yen
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hamilton
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Brett
authors.affiliation: Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University, St. Louis, MO 63110, USA.
authors.forename: Rohit V
authors.initials: RV
authors.lastname: Pappu
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Daisy W
authors.initials: DW
authors.lastname: Leung
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Basler
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA. Electronic address: gamarasinghe@path.wustl.edu.
authors.forename: Gaya K
authors.initials: GK
authors.lastname: Amarasinghe
mesh_terms: D021581:Active Transport, Cell Nucleus; D001667:Binding, Competitive; D002467:Cell Nucleus / Q000378:metabolism; D018360:Crystallography, X-Ray; D029043:Ebolavirus / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D019913:Nuclear Localization Signals; D010750:Phosphoproteins / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism; D028901:alpha Karyopherins / Q000737:chemistry*
chemical_list: C000596544:KPNA5 protein, human; D019913:Nuclear Localization Signals; D010750:Phosphoproteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C446938:VP24 protein, Ebola virus; D014764:Viral Proteins; D028901:alpha Karyopherins