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Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses in autoimmune disorders

ABSTRACT: In this study, we compared the effects of two cytokine treatments on the proteome of human Th-1 cells. We used saturating doses of murine single-chain IL-27 (EBI3+p28, 10nM) and HyperIL-6 (20nM) and continuously stimulated cells of three donors with the two cytokines for 15min or left untreated.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Blood

SUBMITTER: Stephan Wilmes

LAB HEAD: Ignacio Moraga-Gonzalez

PROVIDER: PXD024657 | Pride | 2021-05-05

REPOSITORIES: Pride

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Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses.

Wilmes Stephan S Jeffrey Polly-Anne PA Martinez-Fabregas Jonathan J Hafer Maximillian M Fyfe Paul K PK Pohler Elizabeth E Gaggero Silvia S López-García Martín M Lythe Grant G Taylor Charles C Guerrier Thomas T Launay David D Mitra Suman S Piehler Jacob J Molina-París Carmen C Moraga Ignacio I

eLife 20210419

Cytokines elicit pleiotropic and non-redundant activities despite strong overlap in their usage of receptors, JAKs and STATs molecules. We use IL-6 and IL-27 to ask how two cytokines activating the same signaling pathway have different biological roles. We found that IL-27 induces more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modeling of IL-6 and IL-27 signaling identified STAT3 binding to ...[more]

PMID: 33871355

Similar Datasets

Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses in autoimmune disorders

Project description:In this study, we compared the effects of two cytokine treatments on the proteome of human Th-1 cells. We used saturating doses of murine single-chain IL-27 (EBI3+p28, 10nM) and HyperIL-6 (20nM) and continuously stimulated cells of three donors with the two cytokines for 24h or left untreated.

2021-05-05 | PXD024188 | Pride

IL6-regulated CDk8-mediated phosphoproteome of human primary Th1 cells

Project 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.

2020-12-23 | PXD020964 | Pride

Transcription profiling of human hematopoietic stem cells

Project description:Successful ex vivo expansion of hematopoietic stem cells (HSCs) would greatly benefit the treatment of disease and the understanding of critical questions of stem cell biology. Microarray studies showed that the HSC supportive mouse fetal liver CD3+ cells specifically expressed angiopoietin-like 2 (Angptl2) and angiopoietin-like 3 (Angptl3). When highly enriched HSCs were cultured in the presence of Angptl2 or Angptl3 together with saturating levels of other growth factors for 10 days, a 24 or 30 fold net expansion of long-term HSCs was observed by reconstitution analysis. The coiled-coil domain of Angptl2 mediated the effects of Angptl2 on HSC expansion. Furthermore, angiopoietin-like 5, angiopoietin-like 7, and microfibril-associated glycoprotein 4 also supported expansion of HSCs in culture. Experiment Overall Design: Cultured 3 different cell types Experiment Overall Design: -> Total RNA isolation -> dscDNA -> Biotinylated cRNA -> hybridization to Affymetrix U74Bv2 and U74Cv2 mouse chips

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Sinorhizobium meliloti Ser/Thr/Tyr phosphoproteome

Project description:Sinorhizobium meliloti, a facultative microsymbiont of alfalfa, should fine-tune its cellular processes to live saprophytically in soils characterized with limited nutrients and diverse stresses. In this study, TiO2 enrichment and LC-MS/MS were used to uncover the site-specific Ser/Thr/Tyr phosphoproteome of S. meliloti in minimum medium at stationary phase. There are a total of 96 unique phosphorylated sites, with a Ser/Thr/Tyr distribution of 65:32:5, in 78 proteins. Phosphoproteins identified in S. meliloti showed a wide distribution pattern regarding to functional categories, such as replication, transcription, translation, posttranslational modification, transport and metabolism of amino acids, carbohydrate, inorganic ion, succinoglycan etc. Ser/Thr/Tyr phosphosites identified within the conserved motif in proteins of key cellular function indicate a crucial role of phosphorylation in modulating cellular physiology. Moreover, phosphorylation events potentially involved in rhizobial adaptation to diverse stresses were also discussed, such as those identified in SMa0114 and PhaP2 (polyhydroxybutyrate synthesis), ActR (pH stress and microaerobic adaption), SupA (potassium stress), chaperonin GroEL2 (viability and potentially symbiosis), and ExoP (succinoglycan synthesis and secretion). These Ser/Thr/Tyr phosphosites identified herein would be helpful for our further investigation and understanding of the role of phosphorylation in rhizobial physiology.

2015-10-05 | PXD002064 | Pride

Hg stress

Project description:Effect of HgCl2-treatment (dose-response:15min, 30min, 2h, and 24h) on cellular metabolism, resp on transcription. Differences between BY-4741 (MATa leu2 ura3 his3 met15 can1) + BYstb5 (MATa stb5::canMX4) to gain new insights into Hg-toxicity itself and adaptation to Hg-stress in yeast Saccharomyces cerevisiae.

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2010-09-22 | E-GEOD-24258 | biostudies-arrayexpress

Detection of CHMP2B methylation

Project description:Characterization of CHMP2B methylation by the lysine methyl transferase SMYD2 : identification of the lysine methylated by SMYD2

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M6A IP from BrU-labeled and fragmented nascent RNA.

Project description:M6A immunoprecipitation from 15min BrU labeled and fragmented nascent RNA.

2018-06-19 | GSE114543 | GEO

Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses in autoimmune disorders

Project description:High levels of inflammation are often present in autoimmune diseases and can impact the functioning of the immune system. Specifically, how surrounding inflammation affects cytokine responses has not been extensively studied. We use IL-6 and IL-27, two cytokines playing opposite roles in inflammation, to ask how cytokines adapt to the inflammatory environment. We show that IL-27 induces a more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modelling of IL-6 and IL-27 signaling identify STAT1 (or STAT3) binding dynamics to GP130 (or IL-27R) as the main parameter contributing to sustained pSTAT1 by IL-27. Mutation of Tyr613 on IL-27R decreased IL-27-induced STAT1 phosphorylation by 80%, with limited effect on STAT3 phosphorylation. The strong receptor/STAT coupling by IL-27 led to the induction of a unique gene expression program by this cytokine, which required sustained STAT1 phosphorylation and IRF1 expression and was enriched in classical Interferon Stimulated Genes. Interestingly, the STAT/receptor coupling exhibited by IL-6/IL-27 was altered in Crohn’s disease and SLE patients. IL-6/IL-27 induced a more potent STAT1 activation in SLE patients than in healthy controls, which can be explained by the higher STAT1 expression in these patients. Partial inhibition of JAK activation by sub-saturating doses of Tofacitinib lowered the levels of STAT1 activation by IL-6, representing a new strategy to treat auto-immune disorders where cytokine responses are dysregulated.

2021-04-27 | GSE164479 | GEO

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