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.
- Ignacio Moraga Gonzalez
- Jonathan Martinez-Fabregas
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Philippe IH Bastiaens, Max Planck Institute of Molecular Physiology, Germany
- Received: June 13, 2019
- Accepted: November 24, 2019
- Accepted Manuscript published: November 27, 2019 (version 1)
© 2019, Martinez-Fabregas et al.
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