Department of Microbiology, Mount Sinai School of Medicine, New York, New York, USA.
PLoS Pathog. 2010 Jan 15;6(1):e1000721. doi: 10.1371/journal.ppat.1000721.
Previous studies have demonstrated that Marburg viruses (MARV) and Ebola viruses (EBOV) inhibit interferon (IFN)-alpha/beta signaling but utilize different mechanisms. EBOV inhibits IFN signaling via its VP24 protein which blocks the nuclear accumulation of tyrosine phosphorylated STAT1. In contrast, MARV infection inhibits IFNalpha/beta induced tyrosine phosphorylation of STAT1 and STAT2. MARV infection is now demonstrated to inhibit not only IFNalpha/beta but also IFNgamma-induced STAT phosphorylation and to inhibit the IFNalpha/beta and IFNgamma-induced tyrosine phosphorylation of upstream Janus (Jak) family kinases. Surprisingly, the MARV matrix protein VP40, not the MARV VP24 protein, has been identified to antagonize Jak and STAT tyrosine phosphorylation, to inhibit IFNalpha/beta or IFNgamma-induced gene expression and to inhibit the induction of an antiviral state by IFNalpha/beta. Global loss of STAT and Jak tyrosine phosphorylation in response to both IFNalpha/beta and IFNgamma is reminiscent of the phenotype seen in Jak1-null cells. Consistent with this model, MARV infection and MARV VP40 expression also inhibit the Jak1-dependent, IL-6-induced tyrosine phosphorylation of STAT1 and STAT3. Finally, expression of MARV VP40 is able to prevent the tyrosine phosphorylation of Jak1, STAT1, STAT2 or STAT3 which occurs following over-expression of the Jak1 kinase. In contrast, MARV VP40 does not detectably inhibit the tyrosine phosphorylation of STAT2 or Tyk2 when Tyk2 is over-expressed. Mutation of the VP40 late domain, essential for efficient VP40 budding, has no detectable impact on inhibition of IFN signaling. This study shows that MARV inhibits IFN signaling by a mechanism different from that employed by the related EBOV. It identifies a novel function for the MARV VP40 protein and suggests that MARV may globally inhibit Jak1-dependent cytokine signaling.
先前的研究表明，马尔堡病毒（MARV）和埃博拉病毒（EBOV）抑制干扰素（IFN）-α/β信号转导，但采用不同的机制。EBOV 通过其 VP24 蛋白抑制 IFN 信号转导，该蛋白阻止酪氨酸磷酸化 STAT1 的核积累。相比之下，MARV 感染抑制 IFNα/β诱导的 STAT1 和 STAT2 酪氨酸磷酸化。现在证明，MARV 感染不仅抑制 IFNα/β，还抑制 IFNγ诱导的 STAT 磷酸化，并抑制 IFNα/β和 IFNγ诱导的 Jak 家族激酶的酪氨酸磷酸化。令人惊讶的是，MARV 基质蛋白 VP40 而不是 MARV VP24 蛋白，已被鉴定为拮抗 Jak 和 STAT 酪氨酸磷酸化，抑制 IFNα/β或 IFNγ诱导的基因表达，并抑制 IFNα/β诱导的抗病毒状态。对 IFNα/β和 IFNγ的反应中，STAT 和 Jak 酪氨酸磷酸化的全局丧失使人联想到 Jak1 缺失细胞中观察到的表型。与该模型一致，MARV 感染和 MARV VP40 表达也抑制了 Jak1 依赖性、IL-6 诱导的 STAT1 和 STAT3 酪氨酸磷酸化。最后，MARV VP40 的表达能够防止 Jak1、STAT1、STAT2 或 STAT3 的酪氨酸磷酸化，而 Jak1 激酶的过表达会导致这些蛋白的酪氨酸磷酸化。相比之下，当 Tyk2 过表达时，MARV VP40 不会明显抑制 STAT2 或 Tyk2 的酪氨酸磷酸化。VP40 晚期结构域的突变，对 VP40 出芽至关重要，对 IFN 信号转导的抑制没有明显影响。本研究表明，MARV 通过与相关 EBOV 不同的机制抑制 IFN 信号转导。它确定了 MARV VP40 蛋白的新功能，并表明 MARV 可能全局抑制 Jak1 依赖性细胞因子信号转导。
