Kinetics of cytokine receptor trafficking determine signaling and functional selectivity
-
- Jonathan Martinez-Fabregas
- Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
-
- Stephan Wilmes
- Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
-
- Luopin Wang
- Department Computer Science, Purdue University, West Lafayette, United States
-
- Maximillian Hafer
- Department of Biology, University of Osnabrück, Osnabrück, Germany
-
- Elizabeth Pohler
- Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
-
- Juliane Lokau
- Department of Pathology, Medical Faculty, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
-
- Christoph Garbers
- Department of Pathology, Medical Faculty, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
-
- Adeline Cozzani
- INSERM UMR-S-11721, Centre de Recherche Jean-Pierre Aubert (JPARC), Institut pour la Recherche sur le Cancer de Lille (IRCL), Université de Lille, Lille, France
-
- Paul K Fyfe
- Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
-
- Jacob Piehler
- Department of Biology, University of Osnabrück, Osnabrück, Germany
-
- Majid Kazemian
- Department Computer Science, Purdue University, West Lafayette, United States
-
- Suman Mitra
- INSERM UMR-S-11721, Centre de Recherche Jean-Pierre Aubert (JPARC), Institut pour la Recherche sur le Cancer de Lille (IRCL), Université de Lille, Lille, France
-
- Ignacio Moraga
- Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
抄録
<jats:p>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.</jats:p>
収録刊行物
-
- eLife
-
eLife 8 2019-11-27
eLife Sciences Publications, Ltd