title: Ebola virus VP24 binds karyopherin alpha1 and blocks STAT1 nuclear accumulation.
abstract: Ebola virus (EBOV) infection blocks cellular production of alpha/beta interferon (IFN-alpha/beta) and the ability of cells to respond to IFN-alpha/beta or IFN-gamma. The EBOV VP35 protein has previously been identified as an EBOV-encoded inhibitor of IFN-alpha/beta production. However, the mechanism by which EBOV infection inhibits responses to IFNs has not previously been defined. Here we demonstrate that the EBOV VP24 protein functions as an inhibitor of IFN-alpha/beta and IFN-gamma signaling. Expression of VP24 results in an inhibition of IFN-induced gene expression and an inability of IFNs to induce an antiviral state. The VP24-mediated inhibition of cellular responses to IFNs correlates with the impaired nuclear accumulation of tyrosine-phosphorylated STAT1 (PY-STAT1), a key step in both IFN-alpha/beta and IFN-gamma signaling. Consistent with this proposed function for VP24, infection of cells with EBOV also confers a block to the IFN-induced nuclear accumulation of PY-STAT1. Further, VP24 is found to specifically interact with karyopherin alpha1, the nuclear localization signal receptor for PY-STAT1, but not with karyopherin alpha2, alpha3, or alpha4. Overexpression of VP24 results in a loss of karyopherin alpha1-PY-STAT1 interaction, indicating that the VP24-karyopherin alpha1 interaction contributes to the block to IFN signaling. These data suggest that VP24 is likely to be an important virulence determinant that allows EBOV to evade the antiviral effects of IFNs.
authors.affiliation: Department of Microbiology, Box 1124, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: St Patrick
authors.initials: SP
authors.lastname: Reid
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Leung
authors.forename: Amy L
authors.initials: AL
authors.lastname: Hartman
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Martinez
authors.forename: Megan L
authors.initials: ML
authors.lastname: Shaw
authors.forename: Caroline
authors.initials: C
authors.lastname: Carbonnelle
authors.forename: Viktor E
authors.initials: VE
authors.lastname: Volchkov
authors.forename: Stuart T
authors.initials: ST
authors.lastname: Nichol
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Basler
mesh_terms: D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D029043:Ebolavirus / Q000737:chemistry*; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D014709:Vero Cells; D014764:Viral Proteins / Q000494:pharmacology*; D028901:alpha Karyopherins / Q000187:drug effects / Q000378:metabolism*
chemical_list: D050794:STAT1 Transcription Factor; C446938:VP24 protein, Ebola virus; D014764:Viral Proteins; D028901:alpha Karyopherins