p38 MAPK enhances STAT1-dependent transcription independently of Ser-727 phosphorylation

The transcription factor signal transducer and activator of transcription 1 (STAT1) requires phosphorylation at both Tyr-701 and Ser-727 for full activation. IFN-gamma induces phosphorylation of both residues, whereas stress signals like UV or lipopolysaccharide stimulate phosphorylation of Ser-727 only. Using p38a mitogen-activated protein kinase (MAPK)-deficient cells, we show that the stress-induced phosphorylation of Ser-727 requires p38a MAPK activity, whereas IFN-gamma-stimulated Ser-727 phosphorylation occurs independently of the p38a pathway. Consistently, IFN-gamma stimulated expression of the STAT1 target gene lRF1 to a similar extent in both wild-type and p38a-deficient cells. However, stress-induced activation of the p38 MAPK pathway considerably enhanced the IFN-gamma-induced expression of both the endogenous lRF1 gene and a reporter driven by the IFN-gamma-activated sequence element of the IRF1 promoter. This enhancement occurred independently of increased phosphorylation of Ser-727 by the p38 pathway. Taken together, these results demonstrate an interaction between IFN-gamma signaling and the p38 pathway that leads to increased transcriptional activation by STAT1 independently of phosphorylation at Ser-727.