PXD020964

PXD020964 is an original dataset announced via ProteomeXchange.

Title	IL6-regulated CDk8-mediated phosphoproteome of human primary Th1 cells
Description	Cytokines are highly pleiotropic ligands that critically contribute to a balanced immune response. We have an incomplete understanding of how cytokines elicit their functional pleiotropy, which has limited their therapeutic efficacy. Here, using Interleukin-6 (IL-6) as a model system, we have performed detailed phosphoproteomic and transcriptomic studies in human CD4 + T helper (Th)-1 cells to address the molecular bases defining cytokine functional pleiotropy. We have identified cyclin dependent kinase (CDK)8 as a new negative regulator of transcriptional activities of signal transducer and activator of transcription (STAT)3. We found that CDK8 is a major regulator of the IL-6 phosphoproteome and interacts with STAT3 in the nucleus upon IL-6 stimulation. Inhibition of CDK8 activity, using specific small molecules inhibitors, reduced the IL-6-induced phosphoproteome by 23% in Th-1 cells, including STAT3 S727 phosphorylation. STAT3 binding to target DNA sites in the genome was increased upon CDK8 inhibition, which resulted in a concomitant increase in STAT3 mediated transcriptional activity. Importantly, inhibition of CDK8 activity under Th-17 polarizing conditions resulted in an enhancement of Th-17 differentiation. Our results support a model where CDK8 regulates STAT3 transcriptional processivity via modulation of its gene loci resident time, critically contributing to diversification of IL-6 responses.
HostingRepository	PRIDE
AnnounceDate	2021-04-07
AnnouncementXML	Submission_2021-04-06_23:43:01.661.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jonathan Martinez Fabregas
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-08-17 22:30:10	ID requested
1	2020-12-23 11:13:25	announced
⏵ 2	2021-04-06 23:43:02	announced	2021-04-07: Updated project metadata.

Martinez-Fabregas J, Wang L, Pohler E, Cozzani A, Wilmes S, Kazemian M, Mitra S, Moraga I, CDK8 Fine-Tunes IL-6 Transcriptional Activities by Limiting STAT3 Resident Time at the Gene Loci. Cell Rep, 33(12):108545(2020) [pubmed]

submitter keyword: IL6, MSC2530818, human Th1 cells, CDK8 inhibitor

Ignacio Moraga Gonzalez
contact affiliation	Cell Signaling and Immunology School of Life Sciences University of Dundee
contact email	i.moragagonzalez@dundee.ac.uk
lab head
Jonathan Martinez Fabregas
contact affiliation	Cell Signaling and Immunology
contact email	jmartinezfabregas@dundee.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD020964
     1. Label: PRIDE project
     2. Name: IL6-regulated CDk8-mediated phosphoproteome of human primary Th1 cells