Nature Immunology6, 396 - 402 (2005)
Published online: 27 February 2005; | doi:10.1038/ni1176
The autoimmune suppressor Gadd45 inhibits the T cell alternative p38 activation pathway
Jesus M Salvador1, 3, Paul R Mittelstadt2, Galina I Belova1, Albert J Fornace Jr1, 3
& Jonathan D Ashwell2
1
Gene Response Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
2
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
3
Present addresses: Department of Immunology and Oncology, Centro Nacional de Biotecnologia, Universidad Autonoma de Madrid, Cantoblanco, Madrid 28049, Spain (J.M.S.) and Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA (A.J.F., Jr.).
Correspondence should be addressed to Jonathan D Ashwell jda@pop.nci.nih.gov
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 Gadd45, 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 Gadd45in vitro. Thus, constitutive activation of T cell p38 through the alternative pathway is prevented by Gadd45, the absence of which results in p38 activation, T cell hyperproliferation and autoimmunity.
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inhibits the T cell alternative p38 activation pathway
, 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 Gadd45
