Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain.
Cell Rep. 2019 Apr 16;27(3):847-859.e6. doi: 10.1016/j.celrep.2019.03.060.
Alternative splicing is a prevalent mechanism of gene regulation that is modulated in response to a wide range of extracellular stimuli. Stress-activated protein kinases (SAPKs) play a key role in controlling several steps of mRNA biogenesis. Here, we show that osmostress has an impact on the regulation of alternative splicing (AS), which is partly mediated through the action of p38 SAPK. Splicing network analysis revealed a functional connection between p38 and the spliceosome component SKIIP, whose depletion abolished a significant fraction of p38-mediated AS changes. Importantly, p38 interacted with and directly phosphorylated SKIIP, thereby altering its activity. SKIIP phosphorylation regulated AS of GADD45α, the upstream activator of the p38 pathway, uncovering a negative feedback loop involving AS regulation. Our data reveal mechanisms and targets of SAPK function in stress adaptation through the regulation of AS.
可变剪接是一种普遍的基因调控机制，可响应广泛的细胞外刺激进行调节。应激激活蛋白激酶（SAPKs）在控制 mRNA 生物发生的几个步骤中发挥关键作用。在这里，我们表明渗透压应激会影响可变剪接（AS）的调节，这部分是通过 p38 SAPK 的作用介导的。剪接网络分析显示 p38 与剪接体成分 SKIIP 之间存在功能联系，其耗竭消除了 p38 介导的 AS 变化的显著部分。重要的是，p38 与 SKIIP 相互作用并直接磷酸化 SKIIP，从而改变其活性。SKIIP 磷酸化调节 GADD45α 的 AS，GADD45α 是 p38 途径的上游激活剂，揭示了涉及 AS 调节的负反馈环。我们的数据通过 AS 调节揭示了 SAPK 功能在应激适应中的机制和靶标。
