Instructive roles for cytokine-receptor binding parameters in determining signaling and functional potency
DC Element | Wert | Sprache |
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dc.contributor.author | Moraga, Ignacio | |
dc.contributor.author | Richter, David | |
dc.contributor.author | Wilmes, Stephan | |
dc.contributor.author | Winkelmann, Hauke | |
dc.contributor.author | Jude, Kevin | |
dc.contributor.author | Thomas, Christoph | |
dc.contributor.author | Suhoski, Megan M. | |
dc.contributor.author | Engleman, Edgar G. | |
dc.contributor.author | Piehler, Jacob | |
dc.contributor.author | Garcia, K. Christopher | |
dc.date.accessioned | 2021-12-23T16:12:53Z | - |
dc.date.available | 2021-12-23T16:12:53Z | - |
dc.date.issued | 2015 | |
dc.identifier.issn | 19450877 | |
dc.identifier.uri | https://osnascholar.ub.uni-osnabrueck.de/handle/unios/10315 | - |
dc.description.abstract | Cytokines dimerize cell surface receptors to activate signaling and regulate many facets of the immune response. Many cytokines have pleiotropic effects, inducing a spectrum of redundant and distinct effects on different cell types. This pleiotropy has hampered cytokine-based therapies, and the high doses required for treatment often lead to off-target effects, highlighting the need for a more detailed understanding of the parameters controlling cytokine-induced signaling and bioactivities. Using the prototypical cytokine interleukin-13 (IL-13), we explored the interrelationships between receptor binding and a wide range of downstream cellular responses. We applied structure-based engineering to generate IL-13 variants that covered a spectrum of binding strengths for the receptor subunit IL-13R alpha 1. Engineered IL-13 variants representing a broad range of affinities for the receptor exhibited similar potencies in stimulating the phosphorylation of STAT6 (signal transducer and activator of transcription 6). Delays in the phosphorylation and nuclear translocation of STAT6 were only apparent for those IL-13 variants with markedly reduced affinities for the receptor. From these data, we developed a mechanistic model that quantitatively reproduced the kinetics of STAT6 phosphorylation for the entire spectrum of binding affinities. Receptor endocytosis played a key role in modulating STAT6 activation, whereas the lifetime of receptor-ligand complexes at the plasma membrane determined the potency of the variant for inducing more distal responses. This complex interrelationship between extracellular ligand binding and receptor function provides the foundation for new mechanism-based strategies that determine the optimal cytokine dose to enhance therapeutic efficacy. | |
dc.description.sponsorship | NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01-AI51321]; Howard Hughes Medical InstituteHoward Hughes Medical Institute; American Asthma Foundation; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [SFB 944]; NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [R37AI051321, R01AI051321] Funding Source: NIH RePORTER; This work was supported by the R01-AI51321 from the NIH (K.C.G.), the Howard Hughes Medical Institute (K.C.G.), the American Asthma Foundation (K.C.G.), and SFB 944 from the Deutsche Forschungsgemeinschaft (J.P.). | |
dc.language.iso | en | |
dc.publisher | AMER ASSOC ADVANCEMENT SCIENCE | |
dc.relation.ispartof | SCIENCE SIGNALING | |
dc.subject | AFFINITY | |
dc.subject | Biochemistry & Molecular Biology | |
dc.subject | Cell Biology | |
dc.subject | EXPRESSION | |
dc.subject | GROWTH-HORMONE | |
dc.subject | I INTERFERON RECEPTOR | |
dc.subject | INTERLEUKIN-2 | |
dc.subject | LOW-DOSE IL-2 | |
dc.subject | REGULATORY T-CELLS | |
dc.subject | STRUCTURAL BASIS | |
dc.subject | SURFACE | |
dc.subject | TRAFFICKING | |
dc.title | Instructive roles for cytokine-receptor binding parameters in determining signaling and functional potency | |
dc.type | journal article | |
dc.identifier.doi | 10.1126/scisignal.aab2677 | |
dc.identifier.isi | ISI:000365866800004 | |
dc.description.volume | 8 | |
dc.description.issue | 402 | |
dc.contributor.orcid | 0000-0002-4112-710X | |
dc.contributor.orcid | 0000-0002-3675-5136 | |
dc.contributor.orcid | 0000-0001-9909-0701 | |
dc.contributor.orcid | 0000-0003-3688-6854 | |
dc.contributor.orcid | 0000-0001-7441-1089 | |
dc.identifier.eissn | 19379145 | |
dc.publisher.place | 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA | |
dcterms.isPartOf.abbreviation | Sci. Signal. | |
dcterms.oaStatus | Green Accepted | |
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 14.05.2024