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Structural and functional basis for p38-MK2-activated Rsk signaling in toll-like receptor-stimulated dendritic cells

Rossana Zaru1, Alexander J Edgar1, André Hanauer2

  • 1Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee, United Kingdom.

Molecular and Cellular Biology
|October 22, 2014
PubMed

Insights

Dendritic cells activate Rsk kinases through a noncanonical p38 MAP kinase pathway, distinct from the Erk1/2 pathway. This p38-dependent Rsk activation is crucial for type I interferon production in plasmacytoid dendritic cells.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Ribosomal S6 kinases (Rsk) are key regulators of cellular processes.
  • Rsk activation is typically initiated by Erk1/2 kinases.
  • Dendritic cells utilize a noncanonical pathway involving p38 MAP kinase for Rsk activation.

Purpose of the Study:

  • To investigate the noncanonical activation of Rsk kinases in dendritic cells.
  • To elucidate the role of p38 MAP kinase and its substrates (MK2/3) in Rsk activation.
  • To understand the physiological significance of this pathway in immune cell function.

Main Methods:

  • Comparative analysis of Rsk activation in dendritic cells (DC) and fibroblasts.
  • Assessment of kinase domain function and subcellular localization of p38 and MK2/3.
  • Stimulation of plasmacytoid dendritic cells (pDC) with Toll-like receptor 7 (TLR7) agonists.

Main Results:

  • The Erk1/2-activated C-terminal kinase domain of Rsk is not required for p38-MK2/3 activation.
  • Higher cytosolic localization of p38 and MK2/3 in DC compared to fibroblasts.
  • p38/MK2/3-activated Rsk is essential for type I interferon production in pDC stimulated via TLR7, where Erk1/2 activation is minimal.

Conclusions:

  • Dendritic cells employ a unique MAP kinase signaling cascade for Rsk activation.
  • The p38-MK2/3-Rsk axis plays a critical role in innate immune responses, particularly in pDC.
  • This noncanonical pathway is vital for the production of type I interferons, a key feature of pDC activation.

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