Kinetics of cytokine receptor trafficking determine signaling and functional selectivity
- University of Dundee, United Kingdom
- Purdue University, United States
- University of Osnabrück, Germany
- Otto-von-Guericke-University Magdeburg, Germany
- Université de Lille, France
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.
Data availability
Sequencing data have been deposited in GEO under accession number code: GSE130810
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Kinetics of cytokine receptor trafficking determine signaling and functional selectivityNCBI Gene Expression Omnibus, GSE130810.
Article and author information
Author details
Jonathan Martinez-Fabregas
Ignacio Moraga Gonzalez
Funding
Horizon 2020 Framework Programme (714680)
- Ignacio Moraga Gonzalez
Horizon 2020 Framework Programme (714680)
- Jonathan Martinez-Fabregas
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Martinez-Fabregas et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Kinetics of cytokine receptor trafficking determine signaling and functional selectivity
eLife 8:e49314.
https://doi.org/10.7554/eLife.49314
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