Interferons are a group of signaling proteins that are at the forefront of the innate and adaptive immune systems. When an organism gets infected, they dock on receptors on the cells surface and initiate a cascade of signals that ultimately causes the cell to activate antiviral or antibacterial gene expression. Gene expression itself requires the Mediator complex, a crucial component of transcription initiation. Mediator connects RNA polymerase and gene-specific transcription factors. Like a complex machine it consists of different modules, each with a distinct role. A module containing the kinases CDK8/CDK19 is part of this machine and modifies other molecules. By doing so, it positively or negatively regulates transcription, depending on the gene. This way, the CDK8/CDK19 module precisely adjusts the transcription output to meet the needs.
CDK8 and CDK19 share up to 77% of their amino acid sequences, and have been thought to act like twins, virtually interchangeable and functionally redundant. The team of Pavel Kovarik, in close collaboration with Dylan Taatjes from the University of Colorado Boulder now first set out to identify the distinct functions of the two enzymes by analyzing their role in response to one type of interferon, called interferon gamma. Surprisingly they found out that the two enzymes are more like fraternal twins, highly similar, but functionally and mechanistically distinct. Both CDK8 and CDK19 are key regulators in the interferon gamma response, but activate different sets of genes. Also, only CDK8 acts as a kinase, while CDK19 has a scaffolding function, as first author Iris Steinparzer explains in detail: "Given the high similarity of CDK8 and CDK19, especially within their almost identical kinase domains, we were highly surprised that CDK8 and CDK19 cannot substitute for each other in launching the interferon-induced antiviral program. An even bigger surprise was the finding that CDK8 acts as enzyme (=kinase) while CDK19 does not need its enzymatic activity. We are now curious to figure out the molecular basis for these astonishing differences."
Due to their important role in transcription and also cell proliferation, chemical inhibitors of CDK8 and CDK19 are being tested in medically relevant approaches. The currently available inhibitors target both kinases indiscriminately. The discovery of distinct functions of CDK8 and CDK19 implies that targeting the enzymes separately might decisively improve effectiveness and application of CDK8/CDK19 inhibitors.
Original Publication in Molecular Cell
Iris Steinparzer, Vitaly Sedlyarov, Jonathan D. Rubin, Kevin Eislmayr, Matthew D. Galbraith, Cecilia B. Levandowski, Terezia Vcelkvoa, Lucy Sneezum, Florian Wascher, Fabian Amman, Renata Kleinova, Heather Bender, Zdenek Andrysik, Joaquin M. Espinosa, Giulio Superti-Furga, Robin D. Dowell, Dylan J. Taatjes, Pavel Kovarik: Transcriptional Responses to IFN-γ Require Mediator Kinase-Dependent Pause Release and Mechanistically Distinct CDK8 and CDK19 Functions.