The vaccinia virus-stimulated mitogen-activated protein kinase (MAPK) pathway is required for virus multiplication
The vaccinia virus-stimulated mitogen-activated protein kinase (MAPK) pathway is required for virus multiplication
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DOI：
10.1042/bj20031375
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发表时间：
2004-07-15
影响因子：
4.1
通讯作者：
Bonjardim, CA
中科院分区：
文献类型：
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作者：
Andrade, AA;Silva, PNG;Bonjardim, CA
早期事件在病毒增殖中起决定性作用。我们先前已经表明MAPK/ERK 1/2（促分裂原活化蛋白激酶/细胞外信号调节激酶1/2）和蛋白激酶A的活化对于牛痘病毒（VV）增殖是关键的[de Magalhaes，Andrade，Silva，Sousa，Ropert，Ferreira，Kroon，Gazzinelli和Bonjardim（2001）J.Biol.Chem.276，38353-38360]。在本研究中，我们表明VV感染引起了ERK 1/2和RSK 2（核糖体S6激酶2）的持续激活。我们的研究结果还提供了证据表明，这种模式的激酶激活依赖于病毒增殖和正在进行的蛋白质合成，并保持独立的病毒DNA合成。值得注意的是，VGF（VV生长因子），虽然参与。对于延长ERK 1/2激活不是必需的。此外，我们的研究结果表明，VV刺激的ERK 1/2激活似乎也需要肌动蛋白动力学，微管聚合和酪氨酸激酶磷酸化。VV-刺激的途径MEK/ERK 1/2/RSK 2（其中MEK代表MAPK/ERK激酶）导致三元复合物因子Elk-1的磷酸化和早期生长反应（early growth response，ERK-1）基因的表达，其在动力学上抑制激酶活化。该途径的募集具有生物学相关性，因为其破坏对病毒胸苷激酶基因表达、病毒DNA复制和VV增殖产生深远影响。VV感染后持续的激酶激活模式是独特的。此外，通过连接细胞骨架和酪氨酸激酶产生的上游信号，MEK/ERK 1/2/RSK 2级联似乎不仅在感染的早期阶段（即渗透后）起决定性作用，而且对确定病毒后代的命运也至关重要。
Early events play a decisive role in virus multiplication. We have shown previously that activation of MAPK/ERK1/2 (mitogen-activated protein kinase/extracellular-signal-regulated kinase 1/2) and protein kinase A are pivotal for vaccinia virus (VV) multiplication [de Magalhaes, Andrade, Silva, Sousa, Ropert, Ferreira, Kroon, Gazzinelli and Bonjardim (2001) J. Biol. Chem. 276, 38353-38360]. In the present study, we show that VV infection provoked a sustained activation of both ERK1/2 and RSK2 (ribosomal S6 kinase 2). Our results also provide evidence that this pattern of kinase activation depends on virus multiplication and ongoing protein synthesis and is maintained independently of virus DNA synthesis. It is noteworthy that the VGF (VV growth factor), although involved. is not essential for prolonged ERK1/2 activation. Furthermore, our findings suggest that the VV-stimulated ERK1/2 activation also seems to require actin dynamics, microtubule polymerization and tyrosine kinase phosphorylation. The VV-stimulated pathway MEK/ERK1/2/RSK2 (where MEK stands for MAPK/ERK kinase) leads to phosphorylation of the ternary complex factor Elk-1 and expression of the early growth response (egr-1) gene, which kinetically paralleled the kinase activation. The recruitment of this pathway is biologically relevant, since its disruption caused a profound effect on viral thymidine kinase gene expression, viral DNA replication and VV multiplication. This pattern of sustained kinase activation after VV infection is unique. In addition, by connecting upstream signals generated at the cytoskeleton and by tyrosine kinase, the MEK/ERK1/2/RSK2 cascade seems to play a decisive role not only at early stages of the infection, i.e. post-penetration, but is also crucial to define the fate of virus progeny.