Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses
DC Element | Wert | Sprache |
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dc.contributor.author | Wilmes, Stephan | |
dc.contributor.author | Jeffrey, Polly-Anne | |
dc.contributor.author | Martinez-Fabregas, Jonathan | |
dc.contributor.author | Hafer, Maximillian | |
dc.contributor.author | Fyfe, Paul K. | |
dc.contributor.author | Pohler, Elizabeth | |
dc.contributor.author | Gaggero, Silvia | |
dc.contributor.author | Lopez-Garcia, Martin | |
dc.contributor.author | Lythe, Grant | |
dc.contributor.author | Taylor, Charles | |
dc.contributor.author | Guerrier, Thomas | |
dc.contributor.author | Launay, David | |
dc.contributor.author | Mitra, Suman | |
dc.contributor.author | Piehler, Jacob | |
dc.contributor.author | Molina-Paris, Carmen | |
dc.contributor.author | Moraga, Ignacio | |
dc.date.accessioned | 2021-12-23T16:23:35Z | - |
dc.date.available | 2021-12-23T16:23:35Z | - |
dc.date.issued | 2021 | |
dc.identifier.issn | 2050084X | |
dc.identifier.uri | https://osnascholar.ub.uni-osnabrueck.de/handle/unios/14593 | - |
dc.description.abstract | 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 GP130, and STAT1 binding to IL-27R alpha, as the main dynamical processes contributing to sustained pSTAT1 levels by IL-27. Mutation of Tyr613 on IL-27R alpha decreased IL-27-induced STAT1 phosphorylation by 80% but had limited effect on STAT3 phosphorgylation. Strong receptor/STAT coupling by IL-27 initiated a unique gene expression program, which required sustained STAT1 phosphorylation and IRF1 expression and was enriched in classical Interferon Stimulated Genes. Interestingly, the STAT/receptor coupling exhibited by IL6/IL-27 was altered in patients with systemic lupus erythematosus (SLE). IL-6/IL-27 induced a more potent STAT1 activation in SLE patients than in healthy controls, which correlated with higher STAT1 expression in these patients. Partial inhibition of JAK activation by sub-saturating doses of Tofacitinib specifically lowered the levels of STAT1 activation by IL-6. Our data show that receptor and STATs concentrations critically contribute to shape cytokine responses and generate functional pleiotropy in health and disease. | |
dc.description.sponsorship | NHLBI NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [K22 HL125593] Funding Source: Medline; Wellcome TrustWellcome TrustEuropean Commission [202323/Z/16/Z] Funding Source: Medline | |
dc.language.iso | en | |
dc.publisher | ELIFE SCIENCES PUBLICATIONS LTD | |
dc.relation.ispartof | ELIFE | |
dc.subject | Biology | |
dc.subject | CD4(+) T-CELLS | |
dc.subject | EXPRESSION | |
dc.subject | IL-6 | |
dc.subject | INDUCTION | |
dc.subject | INFLAMMATION | |
dc.subject | INTERFERON | |
dc.subject | INTERLEUKIN-27 | |
dc.subject | Life Sciences & Biomedicine - Other Topics | |
dc.subject | PROLIFERATION | |
dc.subject | PROTEIN | |
dc.subject | SIGNAL TRANSDUCER | |
dc.title | Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses | |
dc.type | journal article | |
dc.identifier.doi | 10.7554/eLife.66014 | |
dc.identifier.isi | ISI:000648514600001 | |
dc.description.volume | 10 | |
dc.contributor.orcid | 0000-0001-9828-6737 | |
dc.contributor.orcid | 0000-0002-4112-710X | |
dc.contributor.orcid | 0000-0001-6476-0402 | |
dc.contributor.orcid | 0000-0001-9909-0701 | |
dc.contributor.orcid | 0000-0003-3833-8595 | |
dc.contributor.orcid | 0000-0003-3541-2294 | |
dc.contributor.orcid | 0000-0002-2685-1108 | |
dc.contributor.orcid | 0000-0001-5809-065X | |
dc.contributor.researcherid | ABG-1274-2021 | |
dc.contributor.researcherid | A-5819-2019 | |
dc.publisher.place | SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND | |
dcterms.isPartOf.abbreviation | eLife | |
dcterms.oaStatus | Green Published, Green Submitted, gold | |
crisitem.author.dept | FB 05 - Biologie/Chemie | - |
crisitem.author.deptid | fb05 | - |
crisitem.author.orcid | 0000-0002-2143-2270 | - |
crisitem.author.parentorg | Universität Osnabrück | - |
crisitem.author.netid | PiJa938 | - |
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geprüft am 08.06.2024