Reid St Patrick, Leung Lawrence W, Hartman Amy L, Martinez Osvaldo, Shaw Megan L, Carbonnelle Caroline, Volchkov Viktor E, Nichol Stuart T, Basler Christopher F
Department of Microbiology, Box 1124, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, USA.
J Virol. 2006 Jun;80(11):5156-67. doi: 10.1128/JVI.02349-05.
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.
埃博拉病毒（EBOV）感染会阻断细胞产生α/β干扰素（IFN-α/β）以及细胞对IFN-α/β或IFN-γ作出反应的能力。EBOV的VP35蛋白先前已被鉴定为EBOV编码的IFN-α/β产生抑制剂。然而，EBOV感染抑制对IFN反应的机制此前尚未明确。在此，我们证明EBOV的VP24蛋白作为IFN-α/β和IFN-γ信号传导的抑制剂发挥作用。VP24的表达导致IFN诱导的基因表达受到抑制，并且IFN无法诱导抗病毒状态。VP24介导的对细胞对IFN反应的抑制与酪氨酸磷酸化的STAT1（PY-STAT1）核积累受损相关，而这是IFN-α/β和IFN-γ信号传导中的关键步骤。与VP24的这一假定功能一致，用EBOV感染细胞也会阻断IFN诱导的PY-STAT1核积累。此外，发现VP24与核转运蛋白α1特异性相互作用，核转运蛋白α1是PY-STAT1的核定位信号受体，但不与核转运蛋白α2、α3或α4相互作用。VP24的过表达导致核转运蛋白α1与PY-STAT1的相互作用丧失，表明VP24与核转运蛋白α1的相互作用导致了对IFN信号传导的阻断。这些数据表明，VP24可能是一个重要的毒力决定因素，使EBOV能够逃避IFN的抗病毒作用。
