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Ebola Virus VP24 Proteins Inhibit the Interaction of NPI-1 Subfamily Karyopherin α Proteins with Activated STAT1

2007; American Society for Microbiology; Volume: 81; Issue: 24 Linguagem: Inglês

10.1128/jvi.01097-07

1098-5514

St. Patrick Reid, Charalampos Valmas, Osvaldo Martinez, Freddy Mauricio Sanchez, Christopher F. Basler,

Viral gastroenteritis research and epidemiology

ABSTRACT The Zaire ebolavirus protein VP24 was previously demonstrated to inhibit alpha/beta interferon (IFN-α/β)- and IFN-γ-induced nuclear accumulation of tyrosine-phosphorylated STAT1 (PY-STAT1) and to inhibit IFN-α/β- and IFN-γ-induced gene expression. These properties correlated with the ability of VP24 to interact with the nuclear localization signal receptor for PY-STAT1, karyopherin α1. Here, VP24 is demonstrated to interact not only with overexpressed but also with endogenous karyopherin α1. Mutational analysis demonstrated that VP24 binds within the PY-STAT1 binding region located in the C terminus of karyopherin α1. In addition, VP24 was found to inhibit PY-STAT1 binding to both overexpressed and endogenous karyopherin α1. 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 α family. We found, in contrast to previous studies, that PY-STAT1 can interact not only with karyopherin α1 but also with karyopherins α5 and α6, which together comprise the NPI-1 subfamily of karyopherin αs. Similarly, all three VP24s bound and inhibited PY-STAT1 interaction with karyopherins α1, α5, and α6. 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-β-induced gene expression in human and mouse cells. These findings suggest that VP24 inhibits interaction of PY-STAT1 with karyopherins α1, α5, or α6 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.