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Ser276 phosphorylation of NF-kB p65 by MSK1 controls SCF expression in inflammation

Laurent Reber1, Linda Vermeulen, Guy Haegeman

  • 1EA3771, Inflammation and Environment in Asthma, Université Louis Pasteur-Strasbourg-I, Faculté de Pharmacie, Illkirch, France.

Plos One
|February 7, 2009
PubMed

Insights

The study reveals that MSK1 kinase activity is crucial for upregulating stem cell factor (SCF) during inflammation by enabling NF-kappaB binding to the SCF gene enhancer, impacting inflammatory responses.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Stem cell factor (SCF) transcription is elevated in inflammatory conditions.
  • This upregulation is linked to NF-kappaB and MAP kinases (p38, ERK) activation.

Purpose of the Study:

  • To elucidate the role of MSK1 in regulating SCF transcription during inflammation.
  • To investigate the mechanism by which MSK1 influences NF-kappaB activity and SCF gene expression.

Main Methods:

  • Utilized cell transfection with MSK1 mutants and siRNA.
  • Employed Chromatin Immunoprecipitation (ChIP) assays.
  • Analyzed NF-kappaB p65 phosphorylation and coactivator binding.

Main Results:

  • MSK1 kinase activity is required for IL-1beta-induced NF-kappaB p65 Ser276 phosphorylation.
  • MSK1 and MAPK inhibition prevent p65, CBP, and MSK1 binding to the SCF gene enhancer.
  • Disruption of NF-kappaB and CBP interaction occurs with p65 S276C mutation.
  • MSK1 inhibition (KD mutant or siRNA) downregulates IL-1beta-induced SCF expression.

Conclusions:

  • MSK1 directly links NF-kappaB p65 phosphorylation at Ser276 to its binding at the SCF intronic enhancer.
  • This mechanism is critical for pathophysiological SCF expression in inflammatory settings.
  • MSK1 is a key regulator of inflammatory SCF production.

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