Ebola virus VP24 proteins inhibit the interaction of NPI-1 subfamily karyopherin alpha proteins with activated STAT1.
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.
Reid
St Patrick
SP
Department of Microbiology, Box 1124, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, USA.
Valmas
Charalampos
C
Martinez
Osvaldo
O
Sanchez
Freddy Mauricio
FM
Basler
Christopher F
CF
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*
C423142:KPNA1 protein, human; D050794:STAT1 Transcription Factor; C446938:VP24 protein, Ebola virus; D014764:Viral Proteins; D028901:alpha Karyopherins