Multiple kinases in the interferon-γ response

Janus kinases (JAKs) and signal transducers and activators of transcription (STAT's) are essential for responses to interferons (IFNs), most cytokines, and some growth factors. JAK/STAT signaling is not, however, sufficient for a full IFN-gamma response. Here, a convenient, robust, and quantitative flow cytometry-based kinome-wide siRNA screen has identified nine additional kinases as required for the IFN-gamma class 11 HLA response, seven for an antiviral response, and two for the cytopathic response to encephalomyocarditis virus (EMCV). As one example, inhibition of the IFNI-gamma response by siRNA to ataxia telangiectasia-mutated (ATM) differentially affects a spectrum of IFN-gamma-stimulated mRNAs, with inhibitions being seen as early as 1 h after IFN-gamma stimulation. The implication of ATM, with its previously recognized function in chromatin cleconclensation, in the control of transcription early in the IFN-gamma response highlights both a role for ATM in cytokine responses and a possible correlation with the chromatin decondensation recently observed in response to IFN-gamma in mammalian cells. This work has, therefore, revealed the simplicity, power, and convenience of quantitative flow cytometry-based siRNA screens, a requirement for ATM and multiple additional kinalses in the IFN-gamma response and a possible requirement for two of these kinases in the cytopathic response to EMCV.