CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response.
Gene regulation by cytokine-activated transcription factors of the signal transducer and activator of transcription (STAT) family requires serine phosphorylation within the transactivation domain (TAD). STAT1 and STAT3 TAD phosphorylation occurs upon promoter binding by an unknown kinase. Here, we show that the cyclin-dependent kinase 8 (CDK8) module of the Mediator complex phosphorylated regulatory sites within the TADs of STAT1, STAT3, and STAT5, including S727 within the STAT1 TAD in the interferon (IFN) signaling pathway. We also observed a CDK8 requirement for IFN-γ-inducible antiviral responses. Microarray analyses revealed that CDK8-mediated STAT1 phosphorylation positively or negatively regulated over 40% of IFN-γ-responsive genes, and RNA polymerase II occupancy correlated with gene expression changes. This divergent regulation occurred despite similar CDK8 occupancy at both S727 phosphorylation-dependent and -independent genes. These data identify CDK8 as a key regulator of STAT1 and antiviral responses and suggest a general role for CDK8 in STAT-mediated transcription. As such, CDK8 represents a promising target for therapeutic manipulation of cytokine responses.
Max F. Perutz Laboratories, University of Vienna, Dr. Bohr-Gasse 9, A-1030 Vienna, Austria.
Joanna
J
Bancerek
Zachary C
ZC
Poss
Iris
I
Steinparzer
Vitaly
V
Sedlyarov
Thaddäus
T
Pfaffenwimmer
Ivana
I
Mikulic
Lars
L
Dölken
Birgit
B
Strobl
Mathias
M
Müller
Dylan J
DJ
Taatjes
Pavel
P
Kovarik
D000818:Animals; D056850:Cyclin-Dependent Kinase 8 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D005786:Gene Expression Regulation / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology*; D015850:Interleukin-6 / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000235:genetics / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D018116:Vesiculovirus / Q000502:physiology
D015850:Interleukin-6; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D007371:Interferon-gamma; D056850:Cyclin-Dependent Kinase 8; D012319:RNA Polymerase II