Kinetics of cytokine receptor trafficking determine signaling and functional selectivity
Autor(en): | Martinez-Fabregas, Jonathan Wilmes, Stephan Wang, Luopin Hafer, Maximillian Pohler, Elizabeth Lokau, Juliane Garbers, Christoph Cozzani, Adeline Fyfe, Paul K. Piehler, Jacob Kazemian, Majid Mitra, Suman Moraga, Ignacio |
Stichwörter: | ACTIVATION; ALPHA; BINDING-PROPERTIES; Biology; DYNAMICS; GLYCOPROTEIN 130; GROWTH-HORMONE; I INTERFERON RECEPTOR; IL-6; INTERLEUKIN-2; Life Sciences & Biomedicine - Other Topics; T-CELLS | Erscheinungsdatum: | 2019 | Herausgeber: | ELIFE SCIENCES PUBLICATIONS LTD | Journal: | ELIFE | Volumen: | 8 | Zusammenfassung: | 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. |
ISSN: | 2050084X | DOI: | 10.7554/eLife.49314 |
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geprüft am 29.04.2024