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The autoimmune suppressor Gadd45α inhibits the T cell alternative p38 activation pathway

Nature Immunology volume 6, pages 396–402 (2005)Cite this article

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 Gadd45α, 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 Gadd45α in vitro. Thus, constitutive activation of T cell p38 through the alternative pathway is prevented by Gadd45α, the absence of which results in p38 activation, T cell hyperproliferation and autoimmunity.

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Figure 1: In unstimulated lymphocytes from Gadd45a−/− mice, p38 is spontaneously active.
Figure 2: The activity of p38 is spontaneously increased in resting T lineage but not B cells from Gadd45a−/− mice.
Figure 3: Upstream MAPKK activation in wild-type and Gadd45a−/− T cells.
Figure 4: Inhibition of p38 by recombinant Gadd45α.
Figure 5: The p38 from resting Gadd45a−/− T cells but not B cells autophosphorylates and is inhibited by recombinant Gadd45α.
Figure 6: Recombinant Gadd45α inhibits the activity of p38 phosphorylated by Zap70 but not MKK6.
Figure 7: Inhibition of Src family kinases reduces spontaneous p38 Tyr323 phosphorylation and p38 activity in Gadd45a−/− T cells to wild-type amounts.

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Acknowledgements

We thank S. Gutkind for critical review of this manuscript.

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Author notes

  1. Jesus M Salvador

    Present address: Department of Immunology and Oncology, Centro Nacional de Biotecnologia, Universidad Autonoma de Madrid, Cantoblanco, Madrid, 28049, Spain

  2. Albert J Fornace Jr

    Present address: Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts, 02115, USA

Authors and Affiliations

  1. Gene Response Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Jesus M Salvador, Galina I Belova & Albert J Fornace Jr

  2. Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Paul R Mittelstadt & Jonathan D Ashwell

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Correspondence to Jonathan D Ashwell.

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Salvador, J., Mittelstadt, P., Belova, G. et al. The autoimmune suppressor Gadd45α inhibits the T cell alternative p38 activation pathway. Nat Immunol 6, 396–402 (2005). https://doi.org/10.1038/ni1176

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