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.

This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2015-64437-P and FEDER, PGC2018-094136-B-I00 and FEDER, BFU2014-52125-REDT, and BFU2014-51672-REDC to F.P.; BFU2017-85152-P and FEDER to E.d.N.; BFU2014-005153 to J.V.), the Catalan Government (2017 SGR 799), the European Research Council (AdvG 670146 to J.V.), the Fundación Botín and the Banco Santander through its Santander Universities Global Division (to F.P. and J.V.), the Unidad de Excelencia Maria de Maeztu (MDM-2014-0370), and the Centre of Excellence Severo Ochoa. F.P. is a recipient of an ICREA Acadèmia (Generalitat de Catalunya).