Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses
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 STA...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-04-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/66014 |
| _version_ | 1811202604002181120 |
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| author | Stephan Wilmes Polly-Anne Jeffrey Jonathan Martinez-Fabregas Maximillian Hafer Paul K Fyfe Elizabeth Pohler Silvia Gaggero Martín López-García Grant Lythe Charles Taylor Thomas Guerrier David Launay Suman Mitra Jacob Piehler Carmen Molina-París Ignacio Moraga |
| author_facet | Stephan Wilmes Polly-Anne Jeffrey Jonathan Martinez-Fabregas Maximillian Hafer Paul K Fyfe Elizabeth Pohler Silvia Gaggero Martín López-García Grant Lythe Charles Taylor Thomas Guerrier David Launay Suman Mitra Jacob Piehler Carmen Molina-París Ignacio Moraga |
| author_sort | Stephan Wilmes |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:41:33Z |
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| id | doaj.art-036f2f9b6d674d24920c5291fa65c2f9 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:41:33Z |
| publishDate | 2021-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-036f2f9b6d674d24920c5291fa65c2f92022-12-22T03:51:18ZengeLife Sciences Publications LtdeLife2050-084X2021-04-011010.7554/eLife.66014Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responsesStephan Wilmes0https://orcid.org/0000-0002-4112-710XPolly-Anne Jeffrey1https://orcid.org/0000-0001-6476-0402Jonathan Martinez-Fabregas2https://orcid.org/0000-0001-5809-065XMaximillian Hafer3https://orcid.org/0000-0003-0853-2637Paul K Fyfe4https://orcid.org/0000-0003-3541-2294Elizabeth Pohler5Silvia Gaggero6Martín López-García7https://orcid.org/0000-0003-3833-8595Grant Lythe8https://orcid.org/0000-0001-7966-5571Charles Taylor9Thomas Guerrier10David Launay11Suman Mitra12Jacob Piehler13https://orcid.org/0000-0002-2143-2270Carmen Molina-París14Ignacio Moraga15https://orcid.org/0000-0001-9909-0701Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, United KingdomDepartment of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, United KingdomDivision of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, United KingdomDepartment of Biology and Centre of Cellular Nanoanalytics, University of Osnabrück, Osnabrück, GermanyDivision of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, United KingdomDivision of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, United KingdomUniversité de Lille, INSERM UMR1277 CNRS UMR9020–CANTHER and Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, FranceDepartment of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, United KingdomDepartment of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, United KingdomDepartment of Statistics, School of Mathematics, University of Leeds, Leeds, United KingdomUniv. Lille, Univ. LilleInserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, FranceUniv. Lille, Univ. LilleInserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, FranceUniversité de Lille, INSERM UMR1277 CNRS UMR9020–CANTHER and Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, FranceDepartment of Biology and Centre of Cellular Nanoanalytics, University of Osnabrück, Osnabrück, GermanyDepartment of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, United Kingdom; T-6 Theoretical Division, Los Alamos National Laboratory, Los Alamos, United StatesDivision of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, United KingdomCytokines 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.https://elifesciences.org/articles/66014cytokinesSLESTATsIL6IL27signaling |
| spellingShingle | Stephan Wilmes Polly-Anne Jeffrey Jonathan Martinez-Fabregas Maximillian Hafer Paul K Fyfe Elizabeth Pohler Silvia Gaggero Martín López-García Grant Lythe Charles Taylor Thomas Guerrier David Launay Suman Mitra Jacob Piehler Carmen Molina-París Ignacio Moraga Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses eLife cytokines SLE STATs IL6 IL27 signaling |
| title | Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses |
| title_full | Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses |
| title_fullStr | Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses |
| title_full_unstemmed | Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses |
| title_short | Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses |
| title_sort | competitive binding of stats to receptor phospho tyr motifs accounts for altered cytokine responses |
| topic | cytokines SLE STATs IL6 IL27 signaling |
| url | https://elifesciences.org/articles/66014 |
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