Title :

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

Author(s) :

Martinez-Fabregas, Jonathan [Auteur]
University of Dundee
Wang, Luopin [Auteur]
Purdue University [West Lafayette]
Pohler, Elizabeth [Auteur]
University of Dundee
Cozzani, Adeline [Auteur]
Institut pour la recherche sur le cancer de Lille [Lille] [IRCL]
Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Wilmes, Stephan [Auteur]
University of Dundee
Kazemian, Majid [Auteur correspondant]
Purdue University [West Lafayette]
Mitra, Suman [Auteur correspondant]
Institut pour la recherche sur le cancer de Lille [Lille] [IRCL]
Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Moraga, Ignacio [Auteur correspondant]
University of Dundee

Journal title :

Cell Reports

Pages :

108545 -

Publisher :

Elsevier Inc

Publication date :

2020-12-22

ISSN :

2211-1247

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

Cytokines are highly pleiotropic ligands that regulate the immune response. Here, using interleukin-6 (IL-6) as a model system, we perform detailed phosphoproteomic and transcriptomic studies in human CD4+ T helper 1 (Th-1) ...
Show more >Cytokines are highly pleiotropic ligands that regulate the immune response. Here, using interleukin-6 (IL-6) as a model system, we perform detailed phosphoproteomic and transcriptomic studies in human CD4+ T helper 1 (Th-1) cells to address the molecular bases defining cytokine functional pleiotropy. We identify CDK8 as a negative regulator of STAT3 transcriptional activities, which interacts with STAT3 upon IL-6 stimulation. Inhibition of CDK8 activity, using specific small molecule inhibitors, reduces the IL-6-induced phosphoproteome by 23% in Th-1 cells, including STAT3 S727 phosphorylation. STAT3 binding to target DNA sites in the genome is increased upon CDK8 inhibition, which results in a concomitant increase in STAT3-mediated transcriptional activity. Importantly, inhibition of CDK8 activity under Th-17 polarizing conditions results in an enhancement of Th-17 differentiation. Our results support a model where CDK8 regulates STAT3 transcriptional processivity by modulation of its gene loci resident time, critically contributing to diversification of IL-6 responses.Show less >

Language :

Anglais

Peer reviewed article :

Oui

Audience :

Internationale

Popular science :

Non

Collections :

• Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277

Source :

Harvested from HAL