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; Suman Mitra; Ignacio Moraga Gonzalez

doi:10.7554/eLife.49314

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

Cell Signalling and Immunology

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25 Citations (Scopus)

106 Downloads (Pure)

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
Article number	e49314
Pages (from-to)	1-32
Number of pages	32
Journal	eLife
Volume	8
DOIs	https://doi.org/10.7554/eLife.49314
Publication status	Published - 27 Nov 2019

Keywords

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

ASJC Scopus subject areas

Immunology and Microbiology(all)
Biochemistry, Genetics and Molecular Biology(all)
Neuroscience(all)

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10.7554/eLife.49314Licence: CC BY

Final Published VersionFinal published version, 5.02 MBLicence: CC BY

Cite this

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title = "Kinetics of cytokine receptor trafficking determine signaling and functional selectivity",

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.",

keywords = "bias signaling, cytokine engineering, cytokine signaling, endosomal traffic, functional pleiotropy, human, immunology, inflammation",

author = "Jonathan Martinez-Fabregas and Stephan Wilmes and Luopin Wang and Maximillian Hafer and Elizabeth Pohler and Juliane Lokau and Christoph Garbers and Adeline Cozzani and Jacob Piehler and Majid Kazemian and Suman Mitra and {Moraga Gonzalez}, Ignacio",

note = "We thank members of the Moraga, Mitra and Kazemian laboratories for helpful advice and discussion. We thank Dynamic Biosensors for their help characterizing IL-6 variants binding properties. This work was supported by the StG, LS6, Wellcome-Trust-202323/Z/16/Z and ERC-206-STG grant (I.M. J.M.F.), by EMBO (S.W. 454-2017) and by the DFG (SFB 944, P8/Z, J.P.) ",

year = "2019",

month = nov,

day = "27",

doi = "10.7554/eLife.49314",

language = "English",

volume = "8",

pages = "1--32",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications Ltd.",

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T1 - Kinetics of cytokine receptor trafficking determine signaling and functional selectivity

AU - Martinez-Fabregas, Jonathan

AU - Wilmes, Stephan

AU - Wang, Luopin

AU - Hafer, Maximillian

AU - Pohler, Elizabeth

AU - Lokau, Juliane

AU - Garbers, Christoph

AU - Cozzani, Adeline

AU - Piehler, Jacob

AU - Kazemian, Majid

AU - Mitra, Suman

AU - Moraga Gonzalez, Ignacio

N1 - We thank members of the Moraga, Mitra and Kazemian laboratories for helpful advice and discussion. We thank Dynamic Biosensors for their help characterizing IL-6 variants binding properties. This work was supported by the StG, LS6, Wellcome-Trust-202323/Z/16/Z and ERC-206-STG grant (I.M. J.M.F.), by EMBO (S.W. 454-2017) and by the DFG (SFB 944, P8/Z, J.P.)

PY - 2019/11/27

Y1 - 2019/11/27

N2 - 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.

AB - 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.

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KW - immunology

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Kinetics of cytokine receptor trafficking determine signaling and functional selectivity

Abstract

Keywords

ASJC Scopus subject areas

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Mapping Cytokine Signalling Networks using Engineered Surrogate Ligands (Sir Henry Dale Fellowship)

Moraga Gonzalez, Ignacio

Cite this

Kinetics of cytokine receptor trafficking determine signaling and functional selectivity

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Projects

Mapping Cytokine Signalling Networks using Engineered Surrogate Ligands (Sir Henry Dale Fellowship)

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Moraga Gonzalez, Ignacio

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