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

Nature Immunologyvolume 6pages396402 (2005) | Download Citation

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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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Acknowledgements

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

Author information

Author notes

    • Jesus M Salvador

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

    • Albert J Fornace Jr

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

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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The authors declare no competing financial interests.

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Correspondence to Jonathan D Ashwell.

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https://doi.org/10.1038/ni1176

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