Functional Network Analysis Reveals the Relevance of SKIIP in the Regulation of Alternative Splicing by p38 SAPK.

Caterina Carbonell, Arnau Ulsamer, Claudia Vivori, Panagiotis Papasaikas, René Böttcher, Manel Joaquin, Belén Miñana, Juan Ramón Tejedor, Eulàlia de Nadal, Juan Valcárcel, Francesc Posas

Journal: Cell reports 2020;27(3):847-859.e6

PMID: 30995481

Free Full Text on Elsevier Science View on PubMed

Abstract

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.

Address: 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 Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona, Spain.; Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona, Spain. Electronic address: [email protected].; 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; Universitat Pompeu Fabra, Dr. Aiguader 88, 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluis Companys 23, 08010 Barcelona, Spain. Electronic address: [email protected].; Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona, Spain. Electronic address: [email protected].

DOI: 10.1016/j.celrep.2019.03.060

Link outs

Free resources

Full Text Sources:

Miscellaneous:

https://assays.cancer.gov/CPTAC-820

Molecular Biology Databases:

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-HLA-B-1

MeSH Terms: Alternative Splicing, Cell Cycle Proteins, HeLa Cells, Humans, Imidazoles, MAP Kinase Kinase 6, Nuclear Receptor Coactivators, Osmotic Pressure, Phosphorylation, Protein Isoforms, Protein Serine-Threonine Kinases, Protein-Tyrosine Kinases, Pyridines, RNA Interference, RNA, Small Interfering, Sodium Chloride, p38 Mitogen-Activated Protein Kinases, Dyrk Kinases