Kinetics of cytokine receptor trafficking determine signaling and functional selectivity
DC Element | Wert | Sprache |
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dc.contributor.author | Martinez-Fabregas, Jonathan | |
dc.contributor.author | Wilmes, Stephan | |
dc.contributor.author | Wang, Luopin | |
dc.contributor.author | Hafer, Maximillian | |
dc.contributor.author | Pohler, Elizabeth | |
dc.contributor.author | Lokau, Juliane | |
dc.contributor.author | Garbers, Christoph | |
dc.contributor.author | Cozzani, Adeline | |
dc.contributor.author | Fyfe, Paul K. | |
dc.contributor.author | Piehler, Jacob | |
dc.contributor.author | Kazemian, Majid | |
dc.contributor.author | Mitra, Suman | |
dc.contributor.author | Moraga, Ignacio | |
dc.date.accessioned | 2021-12-23T16:23:08Z | - |
dc.date.available | 2021-12-23T16:23:08Z | - |
dc.date.issued | 2019 | |
dc.identifier.issn | 2050084X | |
dc.identifier.uri | https://osnascholar.ub.uni-osnabrueck.de/handle/unios/14431 | - |
dc.description.abstract | Cytokines activate signaling via assembly of cell surface receptors, but it is unclear whether modulation of cytokine-receptor binding parameters can modify biological outcomes. We have engineered IL-6 variants with different affinities to gp130 to investigate how cytokine receptor binding dwell-times influence functional selectivity. Engineered IL-6 variants showed a range of signaling amplitudes and induced biased signaling, with changes in receptor binding dwell-times affecting more profoundly STAT1 than STAT3 phosphorylation. We show that this differential signaling arises from defective translocation of ligand-gp130 complexes to the endosomal compartment and competitive STAT1/STAT3 binding to phospho-tyrosines in gp130, and results in unique patterns of STAT3 binding to chromatin. This leads to a graded gene expression response and differences in ex vivo differentiation of Th17, Th1 and Treg cells. These results provide a molecular understanding of signaling biased by cytokine receptors, and demonstrate that manipulation of signaling thresholds is a useful strategy to decouple cytokine functional pleiotropy. | |
dc.description.sponsorship | Horizon 2020 Framework Programme [714680]; EMBOEuropean Molecular Biology Organization (EMBO) [454-2017]; National Heart, Lung, and Blood InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [K22HL125593]; Wellcome TrustWellcome TrustEuropean Commission [202323/Z/16/Z]; Royal SocietyRoyal Society of LondonEuropean Commission [202323/Z/16/Z]; Contrat de Plan Etat Region Hauts de France; Institut pour la Recherche sur le Cancer de Lille; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [SFB 944, P8/Z]; NATIONAL HEART, LUNG, AND BLOOD INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [K22HL125593] Funding Source: NIH RePORTER; Horizon 2020 Framework Programme 714680 Jonathan Martinez-Fabregas Paul K Fyfe Ignacio Moraga; EMBO 454-2017 Stephan Wilmes; National Heart, Lung, and Blood Institute K22HL125593 Majid Kazemian; Wellcome Trust Sir Henry Dale Fellowship 202323/Z/16/Z Elizabeth Pohler Ignacio Moraga; Royal Society Sir Henry Dale Fellowship 202323/Z/16/Z Elizabeth Pohler Ignacio Moraga; Contrat de Plan Etat Region Hauts de France and Institut pour la Recherche sur le Cancer de Lille Suman Mitra; Deutsche Forschungsgemeinschaft SFB 944, P8/Z Jacob Piehler; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. | |
dc.language.iso | en | |
dc.publisher | ELIFE SCIENCES PUBLICATIONS LTD | |
dc.relation.ispartof | ELIFE | |
dc.subject | ACTIVATION | |
dc.subject | ALPHA | |
dc.subject | BINDING-PROPERTIES | |
dc.subject | Biology | |
dc.subject | DYNAMICS | |
dc.subject | GLYCOPROTEIN 130 | |
dc.subject | GROWTH-HORMONE | |
dc.subject | I INTERFERON RECEPTOR | |
dc.subject | IL-6 | |
dc.subject | INTERLEUKIN-2 | |
dc.subject | Life Sciences & Biomedicine - Other Topics | |
dc.subject | T-CELLS | |
dc.title | Kinetics of cytokine receptor trafficking determine signaling and functional selectivity | |
dc.type | journal article | |
dc.identifier.doi | 10.7554/eLife.49314 | |
dc.identifier.isi | ISI:000503011900001 | |
dc.description.volume | 8 | |
dc.contributor.orcid | 0000-0001-5809-065X | |
dc.contributor.orcid | 0000-0003-4939-6950 | |
dc.contributor.orcid | 0000-0001-9909-0701 | |
dc.contributor.orcid | 0000-0001-7080-8820 | |
dc.contributor.orcid | 0000-0003-3541-2294 | |
dc.contributor.orcid | 0000-0001-5758-4092 | |
dc.contributor.orcid | 0000-0002-4112-710X | |
dc.contributor.researcherid | A-5819-2019 | |
dc.contributor.researcherid | D-9932-2015 | |
dc.contributor.researcherid | C-7917-2018 | |
dc.publisher.place | SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND | |
dcterms.isPartOf.abbreviation | eLife | |
dcterms.oaStatus | gold, Green Published, Green Submitted | |
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 15.05.2024