CDK8 Fine-Tunes IL-6 Transcriptional Activities by Limiting STAT3 Resident Time at the Gene Loci

Martínez-Fábregas, Jonathan; Wang, Luopin; Pöhler, Elizabeth; Cozzani, Adeline; Wilmes, Stephan; Kazemian, Majid; Moraga, Ignacio

doi:10.2139/ssrn.3631393

Cited by 3 publications

(6 citation statements)

References 26 publications

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“…In these cases, TF phosphorylation altered its activity (i.e., target gene expression patterns) and/or stability. Additional direct evidence for Mediator kinases regulating of TF function was obtained through the use of CDK8/CDK19 inhibitors [25,71,72] and through chemical genetics, with an engineered CDK8 analog-sensitive cell line [73].…”

Section: Control Of Tf Activitymentioning

confidence: 99%

The Mediator kinase module: an interface between cell signaling and transcription

Luyties

Taatjes

2022

Trends in Biochemical Sciences

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Section: Control Of Tf Activitymentioning

confidence: 99%

The Mediator kinase module: an interface between cell signaling and transcription

Luyties

Taatjes

2022

Trends in Biochemical Sciences

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“…We recently combined high-throughput multiparametric phospho-flow cytometry with unbiased phosphoproteomic studies to obtain a full picture of the IL-6 signalosome in human T cells. This study uncovered a novel role of the nuclear compartment in defining IL-6 responses, via regulation of CDK8 localization [252]. CDK8 regulated STAT3 chromatin binding dwell-time and transcriptional activities, which could have important implications in STAT3 mediated diseases and inflammation.…”

Section: Discussionmentioning

confidence: 90%

“…CDK8 regulated STAT3 chromatin binding dwell-time and transcriptional activities, which could have important implications in STAT3 mediated diseases and inflammation. CDK8 and STAT3 interacted in the nucleus upon IL-6 stimulation, leading to STAT3 Serine phosphorylation [252]. Inhibition of CDK8 resulted in a more sustained STAT3 Tyrosine phosphorylation and nuclear retention upon IL-6 stimulation, which led to a global increase in STAT3 chromatin binding intensity at all STAT3 target sites and augmented Th-17 differentiation [252].…”

Section: Discussionmentioning

confidence: 99%

“…CDK8 and STAT3 interacted in the nucleus upon IL-6 stimulation, leading to STAT3 Serine phosphorylation [252]. Inhibition of CDK8 resulted in a more sustained STAT3 Tyrosine phosphorylation and nuclear retention upon IL-6 stimulation, which led to a global increase in STAT3 chromatin binding intensity at all STAT3 target sites and augmented Th-17 differentiation [252]. However, CDK8 plays a positive role in regulating STAT1 activities in macrophages, highlighting the complex roles that non-STAT signalling pathways play in modulating and controlling cytokine responses [253].…”

Section: Discussionmentioning

confidence: 99%

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Molecular and cellular factors determining the functional pleiotropy of cytokines

2022

Self Cite

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Cytokines are soluble factors vital for mammalian physiology. Cytokines elicit highly pleiotropic activities, characterized by their ability to induce a wide spectrum of functional responses in a diverse range of cell subsets, which makes their study very challenging. Cytokines activate signalling via receptor dimerization/oligomerization, triggering activation of the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) signalling pathway. Given the strong crosstalk and shared usage of key components of cytokine signalling pathways, a long-standing question in the field pertains to how functional diversity is achieved by cytokines. Here, we discuss how biophysicalfor example, ligand-receptor binding affinity and topologyand cellularfor example, receptor, JAK and STAT protein levels, endosomal compartmentparameters contribute to the modulation and diversification of cytokine responses. We review how these parameters ultimately converge into a common mechanism to fine-tune cytokine signalling that involves the control of the number of Tyr residues phosphorylated in the receptor intracellular domain upon cytokine stimulation. This results in different kinetics of STAT activation, and induction of specific gene expression programs, ensuring the generation of functional diversity by cytokines using a limited set of signalling intermediaries. We describe how these first principles of cytokine signalling have been exploited using protein engineering to design cytokine variants with more specific and less toxic responses for immunotherapy.

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“…These proteins share a complex regulatory interplay, and gene ablation studies show that STAT1 and STAT3 often counteract each other or engage shared enhancers (3,18,19). These interactions re-tune the interpretation of cytokine cues and instruct alternate patterns of gene regulation (14,16,(20)(21)(22)(23)(24)(25)(26).…”

Section: Introduction -mentioning

confidence: 99%

Th1 cells alter the inflammatory signature of IL-6 by channeling STAT transcription factors toAlu-like retroelements

Millrine

Figueras

Fernandez

et al. 2022

Preprint

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Cytokine signaling via STAT1 and STAT3 transcription factors supports and maintains tissue homeostasis. However, these signals also promote inflammation-induced tissue injury. To understand how these inflammatory outcomes are shaped, we applied RNA-seq, ChIP-seq, and ATAC-seq to identify the transcriptional output of STAT1 and STAT3 in peritoneal tissues during acute resolving inflammation and inflammation primed to drive fibrosis. Bioinformatics focussed on the transcriptional output of IL-6 in both settings and examined how pro-fibrotic IFNγ-secreting CD4+ T-cells altered the interpretation of STAT1 and STAT3 cytokine cues. In acute resolving inflammation, STAT1 and STAT3 cooperated to drive stromal gene expression affecting antimicrobial immunity and tissue homeostasis. Introduction of IFNγ-secreting CD4+ T-cells altered this transcriptional program and channeled STAT1 and STAT3 to a previously latent GAS motif in Alu-like enhancer sequences. STAT1 and STAT3 binding to this conserved sequence revealed evidence of reciprocal cross-regulation. Genes affiliated with these loci included those involved in pathophysiology. Thus, effector T-cells re-tune the transcriptional output of IL-6 by shaping a regulatory interplay between STAT1 and STAT3 in inflammation.

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CDK8 Fine-Tunes IL-6 Transcriptional Activities by Limiting STAT3 Resident Time at the Gene Loci

Abstract: Highlights d CDK8 regulates IL-6-mediated STAT3 S727 phosphorylation in primary human T cells d CDK8 controls STAT3 activity by limiting its resident time at gene loci d CDK8 inhibition increases IL-6-mediated Th17 differentiation

Cited by 3 publications

References 26 publications

The Mediator kinase module: an interface between cell signaling and transcription

The Mediator kinase module: an interface between cell signaling and transcription

Molecular and cellular factors determining the functional pleiotropy of cytokines

Th1 cells alter the inflammatory signature of IL-6 by channeling STAT transcription factors toAlu-like retroelements

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