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Kinetics of cytokine receptor trafficking determine signaling and functional selectivity

J. Martinez-Fabregas, S. Wilmes, L. Wang, M. Hafer, E. Pohler, J. Lokau, C. Garbers, A. Cozzani, J. Piehler, View ORCID ProfileM. Kazemian, S. Mitra, I. Moraga
doi: https://doi.org/10.1101/638031
J. Martinez-Fabregas
1Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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S. Wilmes
1Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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L. Wang
2Departments of Biochemistry and Computer Science, Purdue University, West Lafayette, IN, USA
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M. Hafer
3Department of Biology and Center for Cellular Nanoanalytics (CellNanOs), University of Osnabrück, Barbarastr. 11, 49076, Osnabrück, Germany
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E. Pohler
1Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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J. Lokau
4Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany
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C. Garbers
4Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany
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A. Cozzani
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J. Piehler
3Department of Biology and Center for Cellular Nanoanalytics (CellNanOs), University of Osnabrück, Barbarastr. 11, 49076, Osnabrück, Germany
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M. Kazemian
2Departments of Biochemistry and Computer Science, Purdue University, West Lafayette, IN, USA
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  • ORCID record for M. Kazemian
  • For correspondence: imoragagonzalez@dundee.ac.uk suman.mitra@inserm.fr kazemian@purdue.edu
S. Mitra
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  • For correspondence: imoragagonzalez@dundee.ac.uk suman.mitra@inserm.fr kazemian@purdue.edu
I. Moraga
1Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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  • For correspondence: imoragagonzalez@dundee.ac.uk suman.mitra@inserm.fr kazemian@purdue.edu
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ABSTRACT

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.

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  • ↵# These authors share senior authorship

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Posted May 15, 2019.
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Kinetics of cytokine receptor trafficking determine signaling and functional selectivity
J. Martinez-Fabregas, S. Wilmes, L. Wang, M. Hafer, E. Pohler, J. Lokau, C. Garbers, A. Cozzani, J. Piehler, M. Kazemian, S. Mitra, I. Moraga
bioRxiv 638031; doi: https://doi.org/10.1101/638031
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Kinetics of cytokine receptor trafficking determine signaling and functional selectivity
J. Martinez-Fabregas, S. Wilmes, L. Wang, M. Hafer, E. Pohler, J. Lokau, C. Garbers, A. Cozzani, J. Piehler, M. Kazemian, S. Mitra, I. Moraga
bioRxiv 638031; doi: https://doi.org/10.1101/638031

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