Influenza viruses (IV) exploit a variety of signaling pathways. Previous studies showed that the rapidly accelerated fibrosarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) pathway is functionally linked to nuclear export of viral ribonucleoprotein (vRNP) complexes, suggesting that vRNP export is a signaling-induced event. However, the underlying mechanism remained completely enigmatic. Here we have dissected the unknown molecular steps of signaling-driven vRNP export. We identified kinases RSK1/2 as downstream targets of virus-activated ERK signaling. While RSK2 displays an antiviral role, we demonstrate a virus-supportive function of RSK1, migrating to the nucleus to phosphorylate nucleoprotein (NP), the major constituent of vRNPs. This drives association with viral matrix protein 1 (M1) at the chromatin, important for vRNP export. Inhibition or knockdown of MEK, ERK or RSK1 caused impaired vRNP export and reduced progeny virus titers. This work not only expedites the development of anti-influenza strategies, but in addition demonstrates converse actions of different RSK isoforms.

流感病毒（IV）利用多种信号传导途径。先前的研究表明，迅速加速的纤维肉瘤/丝裂原激活的蛋白激酶/细胞外信号调节激酶（Raf / MEK / ERK）途径与病毒核糖核蛋白（vRNP）复合物的核输出功能相关，这表明vRNP的输出是一种信号传导-诱发事件。但是，潜在的机制仍然完全是个谜。在这里，我们剖析了信号驱动vRNP输出的未知分子步骤。我们确定激酶RSK1 / 2为病毒激活的ERK信号的下游目标。虽然RSK2显示抗病毒作用，但我们证明了RSK1的病毒支持功能，迁移到细胞核以磷酸化核蛋白（NP），vRNPs的主要成分。这会驱动与染色质上的病毒基质蛋白1（M1）结合，对于vRNP导出很重要。抑制或敲低MEK，ERK或RSK1导致vRNP出口受损并降低了子代病毒滴度。这项工作不仅加快了抗流感策略的发展，而且还证明了不同RSK亚型的相反作用。