CDK8 Kinase Phosphorylates Transcription Factor STAT1 to Selectively Regulate the Interferon Response

Abstract

SummaryGene 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.

Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure

“…Given a 10-fold increase in Cdk8 from forced expression (Figure 1, D and E), we detected a comparably modest 50%-70% increase in Ser/ Thr-Pro phosphorylated protein levels in Cdk8-transgenic total lysates that is well within the normal physiological range observed during postnatal development (Supplemental Figure 2). Furthermore, we did not see an increase in relative phosphorylated Smad2 or Stat1, two validated Cdk8 targets (35)(36)(37).…”

CDK8/19 Mediator kinases potentiate induction of transcription by NFκB

“…4F, matches the previously elucidated mechanisms of the effect of CDK8 on the transcription induced by serum (6), HIF1A (7), or estrogen receptor (8), indicating that Pol II CTD phosphorylation in the context of newly activated genes is the most general mechanism of transcriptional coregulation by CDK8/19. It is not the sole mechanism of regulation by CDK8/ 19, however; other CDK8/19 phosphorylation substrates also have roles in transcription-regulatory effects, such as phosphorylation of SMADs in the TGFβ pathway (10), of E2F1 (which acts as a repressor of β-catenin/TCF transcriptional activity) (28), and of STAT1 in IFNγ-induced transcription (29). Our data do not preclude the possibility that some other CDK8/19 phosphorylation substrates (e.g., STAT1) could complement Pol II CTD phosphorylation in NFκB coregulation by CDK8/19.…”

Important scaffold function of the Janus kinase 2 uncovered by a novel mouse model harboring a Jak2 activation-loop mutation

“…[28][29][30][31] No obvious difference between the wild-type and the mutant variant of Jak2 concerning Stat1-S727 phosphorylation could be detected ( Figure 4A). In contrast, Jak2-deficient MEFs showed no increase in Stat1 S727 phosphorylation upon IFN-g incubation ( Figure 4A).…”