The autoimmune suppressor Gadd45alpha inhibits the T cell alternative p38 activation pathway.
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Salvador JM, Mittelstadt PR, Belova GI, Fornace AJ Jr, Ashwell JD
The autoimmune suppressor Gadd45alpha inhibits the T cell alternative p38 activation pathway.
Nat Immunol. 2005 Apr;6(4):396-402. Epub 2005 Feb 27.
- PubMed ID
- 15735649 [ View in PubMed]
- 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.