Transcription cycle of Stat1-regulated transcription

Stat transcription factors are essential components of the Jak/Stat signaling pathway that governs responses to cytokines. The proposed project will address the role of interferon-induced Stat1 phosphorylation on the residue S727 and the responsible kinase in the transcription cycle. S727 phosphorylation is known to be required for full biological activity of Stat1. We recently reported that in response to interferons Stat1 is S727-phosphorylated only if bound to target gene promoters. This unique mechanism of the transcription factor activation suggests that the still unknown S727 kinase is a chromatin-associated enzyme. Our preliminary data suggest that the cyclin- dependent kinase 8 (CDK8) is the major S727 kinase in interferon-stimulated cells. CDK8 is known to act in chromatin-associated manner by binding and controlling the transcription activator function of the Mediator complex. Both CDK8 and the Mediator complex play an essential role in mammalian gene transcription although the precise functions are still not fully understood. The few so far reported studies suggest that CDK8 can act in the context of the Mediator complex as a molecular switch controlling the frequency of initiation and reinitiation of transcription. Reinitiation is only poorly understood process that is assumed to be critical for the control of inducible gene expression. It is needed to couple the transcription with the intensity and duration of the external cues. The control of reinitiation prevents a prolonged and potentially detrimental transcription after the removal of the external stimulus. In agreement with this, experimental as well as computational models predict that Stat transcription factors require constant cycling from chromatin to the cytokine receptors in order to properly accomplish their biological function. The molecular mechanism regulating this process is not known. We propose that CDK8 phosphorylates Stat1 at S727 thereby facilitating the transcription reinitiation and Stat1 recycling in response to interferons. This hypothesis will be tested also for other Stats known to be serine-phosphorylated in responses to cytokines.

Important switch of immune response identifiedOur body has developed complex defense mechanisms to fight infections by viruses and bacteria, which is critical for our survival. However, the understanding of how the intensity and duration of the immune reactions are coordinated is incomplete. In a study supported by the FWF we, in collaboration with the team of Dylan Taatjes from the University of Colorado in Boulder, now identified a new regulator of the immune system. This regulator may act as molecular switch to properly adjust the immune response. The immune response against invading pathogens is orchestrated by cytokines - small proteins secreted by immune cells upon infection. Cytokines turn on the STAT proteins which have a central role in the regulation of the immune reaction by precisely adjusting the level of the immune response to the right levels. This is crucial to battle viruses and bacteria successfully, while leaving our body unaffected. Several years ago it has been discovered that STATs are regulated by the addition of a specific mark. However, for over ten years it remained unclear how the mark was attached to STATs. Our results now clearly show that the protein CDK8 is responsible for this process and that it is required for proper STAT function and fighting virus infection. The crucial role for CDK8 makes it a highly attractive target for the development of new therapeutics to treat disorders of the immune system. The complex immune reactions sometimes run out control resulting in an immune response without cause, or the absence of immune reaction even though it would be needed. Studying the role of CDK8 in immune disorders will establish if it is a suitable target for drugs that could help patients with immune defects.The results of the study were recently published in the renowned journal Immunity.