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| Subject Categories: Signal Transduction | Immunology |
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| The EMBO Journal
(2004) 23, 1576–1586, doi:10.1038/sj.emboj.7600173 Published online 25 March 2004 |
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GADD45 /GADD45 and MEKK4 comprise a genetic pathway mediating STAT4-independent IFN production in T cells |
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| Hongbo Chi1, Binfeng Lu1, Mutsuhiro Takekawa2, 3, Roger J Davis4 and Richard A Flavell1, 5 |
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1 Section of Immunobiology, Yale University School of Medicine, New Haven, CT, USA 2 Division of Molecular Cell Signaling, Institute of Medical Science, The University of Tokyo, Tokyo, Japan 3 PRESTO, Japan Science and Technology Corporation (JST), Saitama, Japan 4 Howard Hughes Medical Institute and Program in Molecular Medicine, Department of Biochemistry & Molecular Biology, University of Massachusetts Medical School, Worcester, MA, USA 5 Howard Hughes Medical Institute, New Haven, CT, USA To whom correspondence should be addressed Richard A Flavell, Section of Immunobiology, HHMI, Yale University School of Medicine, 300 Cedar Street, TAC S-569, New Haven, CT 06520-8011, USA. Tel.: +1 203 737 2216; Fax: +1 203 737 2958; E-mail: richard.flavell@yale.edu Received 18 November 2003; Accepted 23 February 2004; Published online 25 March 2004. |
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| Abstract |
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| The stress-inducible molecules GADD45 and GADD45 have been implicated in regulating IFN production in CD4 T cells. However, how GADD45 proteins function has been controversial. MEKK4 is a MAP kinase kinase kinase that interacts with GADD45 in vitro. Here we generated MEKK4-deficient mice to define the function and regulation of this pathway. CD4 T cells from MEKK4-/- mice have reduced p38 activity and defective IFN synthesis. Expression of GADD45 or GADD45 promotes IFN production in MEKK4+/+ T cells, but not in MEKK4-/- cells or in cells treated with a p38 inhibitor. Thus, MEKK4 mediates the action of GADD45 and GADD45 on p38 activation and IFN production. During Th1 differentiation, the GADD45/GADD45/MEKK4 pathway appears to integrate upstream signals transduced by both T cell receptor and IL12/STAT4, leading to augmented IFN production in a process independent of STAT4. |
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| Keywords: GADD45, interferon, p38, STAT4, T cell differentiation |
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