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-γ induces phosphorylation of both residues, whereas stress signals like UV or lipopolysaccharide stimulate phosphorylation of Ser-727 only. Using p38α mitogen-activated protein kinase (MAPK)-deficient cells, we show that the stress-induced phosphorylation of Ser-727 requires p38α MAPK activity, whereas IFN-γ-stimulated Ser-727 phosphorylation occurs independently of the p38α pathway. Consistently, IFN-γ stimulated expression of the STAT1 target gene IRF1 to a similar extent in both wild-type and p38α-deficient cells. However, stress-induced activation of the p38 MAPK pathway considerably enhanced the IFN-γ-induced expression of both the endogenous IRF1 gene and a reporter driven by the IFN-γ-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-γ signaling and the p38 pathway that leads to increased transcriptional activation by STAT1 independently of phosphorylation at Ser-727.