Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses
Autor(en): | Wilmes, Stephan Jeffrey, Polly-Anne Martinez-Fabregas, Jonathan Hafer, Maximillian Fyfe, Paul K. Pohler, Elizabeth Gaggero, Silvia Lopez-Garcia, Martin Lythe, Grant Taylor, Charles Guerrier, Thomas Launay, David Mitra, Suman Piehler, Jacob Molina-Paris, Carmen Moraga, Ignacio |
Stichwörter: | Biology; CD4(+) T-CELLS; EXPRESSION; IL-6; INDUCTION; INFLAMMATION; INTERFERON; INTERLEUKIN-27; Life Sciences & Biomedicine - Other Topics; PROLIFERATION; PROTEIN; SIGNAL TRANSDUCER | Erscheinungsdatum: | 2021 | Herausgeber: | ELIFE SCIENCES PUBLICATIONS LTD | Journal: | ELIFE | Volumen: | 10 | Zusammenfassung: | 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-27R alpha, as the main dynamical processes contributing to sustained pSTAT1 levels by IL-27. Mutation of Tyr613 on IL-27R alpha 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 IL6/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. |
ISSN: | 2050084X | DOI: | 10.7554/eLife.66014 |
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geprüft am 29.04.2024