The autoimmune suppressor Gadd45 inhibits the T cell alternative p38 activation pathway (Nature Immunology, 6:396-402, April 2005)

報告日期: 2005/10/11
報告時間: 16:00/16:50
報告學生: 林裕萍
講評老師: 林以行
附件下載:

The autoimmune suppressor Gadd45a inhibits the T cell alternative p38 activation pathway

Nature immunology. 6, 396-402 (2005)

Speaker: 林裕萍                            

Commentator: 林以行 老師                  

Time: 2005/10/11 16:00~16:50

Place: Room 602

 

Abstract:

  The signaling-responsive MAP kinase p38 is a key mediator in immune response. Inhibition of p38 is beneficial in autoimmune diseases such as rheumatoid arthritis. Conventional, p38 is phosphorylayed by upstream MAPK kinases and activated by dual phosphorylation at residues Thr180 and Tyr182. Recently, the authors showed that stimulation of T cells through their antigen receptors activated p38 via an “alternative pathway”.  In this pathway, TCR ligation increased Lck and Zap70 activity, followed by phosphorylation of p38 Tyr323 and subsequent autophosphorylation of Thr180-X-Tyr182 motif. The Gadd45a (growth arrest and DNA damage-induced gene) is a small p38 binding protein, and mice lacking of Gadd45a leads to the development of a lupus-like syndrome. In this study, the authors sought to determine whether Gadd45a deficiency might result in aberrant p38 activation. To their surprise, the p38 was constitutively active in resting Gadd45a-/- T cells but not in B cells, and this increased p38 activity did not result from upstream MAPKK activation. The phosphorylation of p38 Tyr323 in resting Gadd45a-/- T cells was higher than those isolated from wild-type mice. Moreover, recombinant Gadd45a inhibited the Tyr323 phosphorylation and p38 activation by Zap70. In summary, T cells p38 is constitutive activated through the alternative pathway and that may result in T cell hyperproliferation and autoimmunity in the absence of Gadd45a.

 

References:

1.  Salvador, J.M. et al. Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases. Nat. Immunol. 6, 390-395 (2005)

2.  Rudd, C.E. MAPK p38: alternative and nonstressful in T cells. Nat. Immunol. 6, 368-370 (2005)