Kinetics of cytokine receptor trafficking determine signaling and functional selectivity

Jonathan Martinez-Fabregas, Stephan Wilmes, Luopin Wang, Maximillian Hafer, Elizabeth Pohler, Juliane Lokau, Christoph Garbers, Adeline Cozzani, Jacob Piehler, Majid Kazemian (Lead / Corresponding author), Suman Mitra (Lead / Corresponding author), Ignacio Moraga Gonzalez

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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 languageEnglish
Article numbere49314
Pages (from-to)1-32
Number of pages32
JournaleLife
Volume8
DOIs
Publication statusPublished - 27 Nov 2019

Keywords

  • bias signaling
  • cytokine engineering
  • cytokine signaling
  • endosomal traffic
  • functional pleiotropy
  • human
  • immunology
  • inflammation

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