The Autoimmune Suppressor Gadd45alpha Inhibits the T Cell Alternative p38 Activation Pathway

Nat Immunol. 2005 Apr;6(4):396-402. doi: 10.1038/ni1176. Epub 2005 Feb 27.

Abstract

The p38 MAP kinase (MAPK) is phosphorylated and activated by upstream MAPK kinases. T cells have an alternative pathway in which T cell receptor-activated tyrosine kinase Zap70 phosphorylates p38 on Tyr323. Mice lacking Gadd45alpha, a small p38-binding molecule, develop a lupus-like autoimmune disease. Here we show that resting T cells but not B cells from Gadd45a(-/-) mice had spontaneously increased p38 activity in the absence of 'upstream' MAPK kinase activation. The p38 from resting Gadd45a(-/-) T cells was spontaneously phosphorylated on Tyr323, and its activity was specifically inhibited by recombinant Gadd45alpha in vitro. Thus, constitutive activation of T cell p38 through the alternative pathway is prevented by Gadd45alpha, the absence of which results in p38 activation, T cell hyperproliferation and autoimmunity.

MeSH terms

  • Animals
  • Cell Cycle Proteins / immunology*
  • Cell Cycle Proteins / metabolism
  • Enzyme Activation
  • MAP Kinase Signaling System / immunology*
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / immunology*
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Protein-Tyrosine Kinases / immunology
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Antigen, T-Cell / immunology
  • T-Lymphocytes / enzymology*
  • T-Lymphocytes / immunology*
  • Tyrosine / immunology
  • Tyrosine / metabolism
  • ZAP-70 Protein-Tyrosine Kinase
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / immunology
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Cell Cycle Proteins
  • Gadd45a protein, mouse
  • Nuclear Proteins
  • Receptors, Antigen, T-Cell
  • Tyrosine
  • Protein-Tyrosine Kinases
  • ZAP-70 Protein-Tyrosine Kinase
  • Zap70 protein, mouse
  • p38 Mitogen-Activated Protein Kinases