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

Cell Rep. 2019 Apr 16;27(3):847-859.e6. doi: 10.1016/j.celrep.2019.03.060.

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.

Keywords: GADD45; alternative splicing; cell signaling; p38 SAPK; stress responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing* / drug effects
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Dyrk Kinases
  • HeLa Cells
  • Humans
  • Imidazoles / pharmacology
  • MAP Kinase Kinase 6 / metabolism
  • Nuclear Receptor Coactivators / antagonists & inhibitors
  • Nuclear Receptor Coactivators / genetics
  • Nuclear Receptor Coactivators / metabolism*
  • Osmotic Pressure
  • Phosphorylation
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Pyridines / pharmacology
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Sodium Chloride / pharmacology
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Cell Cycle Proteins
  • GADD45A protein, human
  • Imidazoles
  • Nuclear Receptor Coactivators
  • Protein Isoforms
  • Pyridines
  • RNA, Small Interfering
  • SNW1 protein, human
  • Sodium Chloride
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 6
  • MAP2K6 protein, human
  • SB 203580