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

Jonathan Martinez-Fabregas (1) , Luopin Wang (2) , Elizabeth Pohler (1) , Adeline Cozzani (3, 4) , Stephan Wilmes (1) , Majid Kazemian (2) , Suman Mitra (3, 4) , Ignacio Moraga (1)

1 University of Dundee
2 Purdue University [West Lafayette]
3 CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
4 IRCL - Institut pour la recherche sur le cancer de Lille [Lille]

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.

Domaines: Sciences du Vivant [q-bio]

Jonathan Martinez-Fabregas, Luopin Wang, Elizabeth Pohler, Adeline Cozzani, Stephan Wilmes, et al.. CDK8 Fine-Tunes IL-6 Transcriptional Activities by Limiting STAT3 Resident Time at the Gene Loci. Cell Reports, 2020, 33, pp.108545 -. ⟨10.1016/j.celrep.2020.108545⟩. ⟨hal-03492639⟩