Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome.

As Mediator-associated kinases, CDK8 and CDK19 are established regulators of RNA polymerase II transcription; however, the "downstream" biochemical impacts of CDK8/CDK19 inhibition have not been thoroughly examined. We previously showed that CDK8 and CDK19 help activate transcriptional responses to the universal cytokine IFNγ; others have demonstrated that Down syndrome (DS) is characterized by hyperactive IFNγ signaling, which contributes to DS-associated pathologies. Here, we discovered CDK8/CDK19 inhibition drives "downstream" metabolic changes that can reinforce and propagate anti-inflammatory responses independent of transcription. We also identified a new means by which CDK8/CDK19 regulate gene expression, via alternative splicing, and inhibition selectively impacted IFNγ response genes. Collectively, our results establish that Mediator kinase inhibition antagonizes hyperactive IFN signaling in DS, suggesting novel therapeutic strategies.