PT  - JOURNAL ARTICLE
AU  - J. Martinez-Fabregas
AU  - S. Wilmes
AU  - L. Wang
AU  - M. Hafer
AU  - E. Pohler
AU  - J. Lokau
AU  - C. Garbers
AU  - A. Cozzani
AU  - J. Piehler
AU  - M. Kazemian
AU  - S. Mitra
AU  - I. Moraga
TI  - Kinetics of cytokine receptor trafficking determine signaling and functional selectivity
AID  - 10.1101/638031
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 638031
4099  - http://biorxiv.org/content/early/2019/05/15/638031.short
4100  - http://biorxiv.org/content/early/2019/05/15/638031.full
AB  - Cytokines activate downstream signaling networks via assembly of cell surface receptors, but it is unclear whether modulation of cytokine-receptor binding parameters can modify biological outcomes. We have engineered variants of IL-6 with different affinities to the gp130 receptor chain to investigate how cytokine receptor binding kinetics influence functional selectivity. Engineered IL-6 variants showed a range of signaling amplitudes, from minimal to full agonist, and induced biased signaling, with changes in receptor binding kinetics 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, in turn, leads to a graded gene expression response and substantial 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.