Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Morinobu, A. et al.

Morinobu, Gadina, Strober, Visconti, Fornace, Montagna, Feldman, Nishikomori, O'Shea,

STAT4 serine phosphorylation is critical for IL-12- induced IFN-gamma production but not for cell proliferation.

T helper 1 (T(H)1) differentiation and IFN-gamma production are crucial in cell-mediated immune responses. IL-12 is an important regulator of this process and mediates its effects through signal transducer and activator of transcription 4 (STAT4). IFN-gamma production is also regulated by the p38 mitogen-activated kinase pathway, although the mechanisms are ill-defined. We show here that GADD45-beta and GADD45-gamma can induce STAT4 S721 phosphorylation via the MKK6/p38 pathway. Thus, STAT4 could be a target that accounts for the defects in cell-mediated immunity associated with perturbations in the p38 pathway. To investigate the biological significance of STAT4 S721 phosphorylation, we reconstituted primary spleen cells from STAT4-deficient mice with wild-type and mutated STAT4, by using a retroviral gene transduction. We demonstrated that expression of wild-type STAT4, but not the S721A mutant, restored normal T(H)1 differentiation and IFN-gamma synthesis. The inability of STAT4 S721 to restore IFN-gamma production was not caused by decreased IL-12R expression because the STAT4 S721 mutant also failed to restore IFN-gamma production in STAT4-deficient IL-12Rbeta2 transgenic cells. Importantly, STAT4 S721A-transduced cells showed normal proliferative response to IL-12, illustrating that serine phosphorylation is not required for IL-12-induced proliferation. Additionally, the results imply the existence of STAT4 serine phosphorylation-dependent and -independent target genes. We conclude that phosphorylation of STAT4 on both tyrosine and serine residues is important in promoting normal T(H)1 differentiation and IFN-gamma secretion.[1]

References

STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Morinobu, A., Gadina, M., Strober, W., Visconti, R., Fornace, A., Montagna, C., Feldman, G.M., Nishikomori, R., O'Shea, J.J. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]

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