Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses
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- Stephan Wilmes
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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- Polly-Anne Jeffrey
- Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, United Kingdom
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- Jonathan Martinez-Fabregas
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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- Maximillian Hafer
- Department of Biology and Centre of Cellular Nanoanalytics, University of Osnabrück, Osnabrück, Germany
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- Paul K Fyfe
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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- Elizabeth Pohler
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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- Silvia Gaggero
- Université de Lille, INSERM UMR1277 CNRS UMR9020–CANTHER and Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France
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- Martín López-García
- Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, United Kingdom
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- Grant Lythe
- Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, United Kingdom
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- Charles Taylor
- Department of Statistics, School of Mathematics, University of Leeds, Leeds, United Kingdom
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- Thomas Guerrier
- Univ. Lille, Univ. LilleInserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France
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- David Launay
- Univ. Lille, Univ. LilleInserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France
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- Suman Mitra
- Université de Lille, INSERM UMR1277 CNRS UMR9020–CANTHER and Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France
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- Jacob Piehler
- Department of Biology and Centre of Cellular Nanoanalytics, University of Osnabrück, Osnabrück, Germany
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- Carmen Molina-París
- Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, United Kingdom
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- Ignacio Moraga
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
抄録
<jats:p>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 modeling 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 phosphorgylation. 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.</jats:p>
収録刊行物
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- eLife
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eLife 10 e66014-, 2021-04-19
eLife Sciences Publications, Ltd