Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade
Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade
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DOI：
10.1038/35060098
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发表时间：
2001-03-01
影响因子：
21.3
通讯作者：
Ludwig, S
中科院分区：
文献类型：
--
作者：
Pleschka, S;Wolff, T;Ludwig, S
甲型流感病毒是世界范围内人类和不同动物物种的重要病原体。这种负链RNA病毒的十种不同病毒蛋白中的大多数功能已被很好地阐明(1)。然而，对病毒诱导的支持病毒复制的细胞内信号事件知之甚少。Raf/MEK/ERK级联信号通路是丝裂原活化蛋白(MAP)信号通路的原型，在细胞的生长、分化和存活过程中起着重要作用(2-5)。通过鉴定特定的抑制剂，如U0126，可以在MAPK/ERK激酶(MEK)(6-8)的水平上阻断该级联反应，从而促进了对该通路功能的研究。在这里，我们表明，感染甲型流感病毒的细胞导致Raf/MEK/ERK级联的双相激活。抑制Raf信号会导致病毒核糖核蛋白复合体(RNPs)的核滞留，核输出蛋白(NEP/NS2)的功能受损，并伴随着病毒生产的抑制。因此，在病毒生命周期中，通过有丝分裂级联信号似乎对病毒生产和RNP从细胞核输出是必不可少的。
Influenza A viruses are important worldwide pathogens in humans and different animal species. The functions of most of the ten different viral proteins of this negative-strand RNA virus have been well elucidated(1). However, little is known about the virus-induced intracellular signalling events that support viral replication. The Raf/MEK/ERK cascade is the prototype of mitogen-activated protein (MAP) kinase cascades and has an important role in cell growth, differentiation and survival(2-5). investigation of the function of this pathway has been facilitated by the identification of specific inhibitors such as U0126, which blocks the cascade at the level of MAPK/ERK kinase (MEK)(6-8). Here we show that infection of cells with influenza A virus leads to biphasic activation of the Raf/MEK/ERK cascade. Inhibition of Raf signalling results in nuclear retention of viral ribonucleoprotein complexes (RNPs), impaired function of the nuclear-export protein (NEP/NS2) and concomitant inhibition of virus production. Thus, signalling through the mitogenic cascade seems to be essential for virus production and RNP export from the nucleus during the viral life cycle.