title: Ebola virus VP24 proteins inhibit the interaction of NPI-1 subfamily karyopherin alpha proteins with activated STAT1.
abstract: The Zaire ebolavirus protein VP24 was previously demonstrated to inhibit alpha/beta interferon (IFN-alpha/beta)- and IFN-gamma-induced nuclear accumulation of tyrosine-phosphorylated STAT1 (PY-STAT1) and to inhibit IFN-alpha/beta- and IFN-gamma-induced gene expression. These properties correlated with the ability of VP24 to interact with the nuclear localization signal receptor for PY-STAT1, karyopherin alpha1. Here, VP24 is demonstrated to interact not only with overexpressed but also with endogenous karyopherin alpha1. Mutational analysis demonstrated that VP24 binds within the PY-STAT1 binding region located in the C terminus of karyopherin alpha1. In addition, VP24 was found to inhibit PY-STAT1 binding to both overexpressed and endogenous karyopherin alpha1. We assessed the binding of both PY-STAT1 and the VP24 proteins from Zaire, mouse-adapted Zaire, and Reston Ebola viruses for interaction with all six members of the human karyopherin alpha family. We found, in contrast to previous studies, that PY-STAT1 can interact not only with karyopherin alpha1 but also with karyopherins alpha5 and alpha6, which together comprise the NPI-1 subfamily of karyopherin alphaS. Similarly, all three VP24s bound and inhibited PY-STAT1 interaction with karyopherins alpha1, alpha5, and alpha6. Consistent with their ability to inhibit the karyopherin-PY-STAT1 interaction, Zaire, mouse-adapted Zaire, and Reston Ebola virus VP24s displayed similar capacities to inhibit IFN-beta-induced gene expression in human and mouse cells. These findings suggest that VP24 inhibits interaction of PY-STAT1 with karyopherins alpha1, alpha5, or alpha6 by binding within the PY-STAT1 binding region of the karyopherins and that this function is conserved among the VP24 proteins of different Ebola virus species.
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: Charalampos
authors.initials: C
authors.lastname: Valmas
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Martinez
authors.forename: Freddy Mauricio
authors.initials: FM
authors.lastname: Sanchez
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Basler
mesh_terms: D000818:Animals; D002460:Cell Line; D029043:Ebolavirus / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D050794:STAT1 Transcription Factor / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D028901:alpha Karyopherins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*
chemical_list: C423142:KPNA1 protein, human; D050794:STAT1 Transcription Factor; C446938:VP24 protein, Ebola virus; D014764:Viral Proteins; D028901:alpha Karyopherins