Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses

  1. Stephan Wilmes
  2. Polly-Anne Jeffrey
  3. Jonathan Martinez-Fabregas
  4. Maximillian Hafer
  5. Paul K Fyfe
  6. Elizabeth Pohler
  7. Silvia Gaggero
  8. Martin Lopez-Garcia
  9. Grant Lythe
  10. Charles Taylor
  11. Thomas Guerrier
  12. David Launay
  13. Suman Mitra
  14. Jacob Piehler
  15. Carmen Molina-Paris  Is a corresponding author
  16. Ignacio Moraga Gonzalez  Is a corresponding author
  1. University of Dundee, United Kingdom
  2. University of Leeds, United Kingdom
  3. University of Osnabrück, Germany
  4. Université de Lille, France
  5. Universität Osnabrück, Germany

Abstract

Cytokines elicit pleiotropic and non-redundant activities despite strong overlap in their usage of receptors, JAKs and STATs molecules. We use IL-6 and IL-27 to ask how two cytokines activating the same signaling pathway have different biological roles. We found that IL-27 induces more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modelling of IL-6 and IL-27 signaling identified STAT3 binding to GP130, and STAT1 binding to IL-27Rα, as the main dynamical processes contributing to sustained pSTAT1 levels by IL-27. Mutation of Tyr613 on IL-27Rα decreased IL-27-induced STAT1 phosphorylation by 80% but had limited effect on STAT3 phosphorylation. Strong receptor/STAT coupling by IL-27 initiated a unique gene expression program, which required sustained STAT1 phosphorylation and IRF1 expression and was enriched in classical Interferon Stimulated Genes. Interestingly, the STAT/receptor coupling exhibited by IL-6/IL-27 was altered in patients with systemic lupus erythematosus (SLE). IL-6/IL-27 induced a more potent STAT1 activation in SLE patients than in healthy controls, which correlated with higher STAT1 expression in these patients. Partial inhibition of JAK activation by sub-saturating doses of Tofacitinib specifically lowered the levels of STAT1 activation by IL-6. Our data show that receptor and STATs concentrations critically contribute to shape cytokine responses and generate functional pleiotropy in health and disease.

Data availability

Python (version 3.7) codes for the ABC-SMC model selection and parameter inference can be found in the public repository "https://github.com/PollyJeffrey/Cytokine_modelling", along with the results of the analysis. Phospho-proteomic and proteomic datasets were uploaded to the Proteome Exchange platform with accession numbers PXD024657 and PXD024188 respectively. RNA-seq dataset was uploaded in the GSE database with accession number GSE164479.

The following data sets were generated

Article and author information

Author details

  1. Stephan Wilmes

    Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4112-710X
  2. Polly-Anne Jeffrey

    Department of Applied Mathematics, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6476-0402
  3. Jonathan Martinez-Fabregas

    Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5809-065X
  4. Maximillian Hafer

    Department of Biology, University of Osnabrück, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0853-2637
  5. Paul K Fyfe

    Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3541-2294
  6. Elizabeth Pohler

    Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Silvia Gaggero

    CANTHER and Institut pour la Recherche sur le Cancer de Lille, Université de Lille, Lille, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Martin Lopez-Garcia

    Department of Applied Mathematics, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Grant Lythe

    Department of Applied Mathematics, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Charles Taylor

    Department of Applied Mathematics, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Thomas Guerrier

    INFINITE - Institute for Translational Research in Inflammation, Université de Lille, Lille, France
    Competing interests
    The authors declare that no competing interests exist.
  12. David Launay

    INFINITE - Institute for Translational Research in Inflammation, Université de Lille, Lille, France
    Competing interests
    The authors declare that no competing interests exist.
  13. Suman Mitra

    CANTHER and Institut pour la Recherche sur le Cancer de Lille, Université de Lille, Lille, France
    Competing interests
    The authors declare that no competing interests exist.
  14. Jacob Piehler

    Department of Biology/Chemistry, Universität Osnabrück, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2143-2270
  15. Carmen Molina-Paris

    Department of Applied Mathematics, University of Leeds, Leeds, United Kingdom
    For correspondence
    C.MolinaParis@leeds.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  16. Ignacio Moraga Gonzalez

    Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
    For correspondence
    imoragagonzalez@dundee.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9909-0701

Funding

Horizon 2020 Framework programme (714680)

  • Stephan Wilmes
  • Jonathan Martinez-Fabregas
  • Paul K Fyfe
  • Ignacio Moraga Gonzalez

Wellcome Trust (202323/Z/16/Z)

  • Stephan Wilmes
  • Ignacio Moraga Gonzalez

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: This study was authorized by the French Competent Authority dealing with Research on Human Biological Samples namely the French Ministry of Research. The Authorization number is ECH 19/04. all patients gave their written informed consent

Reviewing Editor

  1. Frederik Graw, Heidelberg University, Germany

Publication history

  1. Received: December 22, 2020
  2. Accepted: April 18, 2021
  3. Accepted Manuscript published: April 19, 2021 (version 1)
  4. Version of Record published: May 5, 2021 (version 2)

Copyright

© 2021, Wilmes et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Stephan Wilmes
  2. Polly-Anne Jeffrey
  3. Jonathan Martinez-Fabregas
  4. Maximillian Hafer
  5. Paul K Fyfe
  6. Elizabeth Pohler
  7. Silvia Gaggero
  8. Martin Lopez-Garcia
  9. Grant Lythe
  10. Charles Taylor
  11. Thomas Guerrier
  12. David Launay
  13. Suman Mitra
  14. Jacob Piehler
  15. Carmen Molina-Paris
  16. Ignacio Moraga Gonzalez
(2021)
Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses
eLife 10:e66014.
https://doi.org/10.7554/eLife.66014

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