Projects per year
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.
Original language | English |
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Article number | e49314 |
Pages (from-to) | 1-32 |
Number of pages | 32 |
Journal | eLife |
Volume | 8 |
DOIs | |
Publication status | Published - 27 Nov 2019 |
Keywords
- bias signaling
- cytokine engineering
- cytokine signaling
- endosomal traffic
- functional pleiotropy
- human
- immunology
- inflammation
ASJC Scopus subject areas
- General Immunology and Microbiology
- General Biochemistry,Genetics and Molecular Biology
- General Neuroscience
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Dive into the research topics of 'Kinetics of cytokine receptor trafficking determine signaling and functional selectivity'. Together they form a unique fingerprint.Projects
- 1 Finished
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Mapping Cytokine Signalling Networks using Engineered Surrogate Ligands (Sir Henry Dale Fellowship)
Crocker, P. (Investigator) & Moraga Gonzalez, I. (Investigator)
1/09/16 → 31/08/22
Project: Research