Competitive binding of stats to receptor phospho-tyr motifs accounts for altered cytokine responses - Université de Lille Accéder directement au contenu
Article Dans Une Revue eLife Année : 2021

Competitive binding of stats to receptor phospho-tyr motifs accounts for altered cytokine responses

Résumé

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.
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hal-04423993 , version 1 (29-01-2024)

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Stephan Wilmes, Polly-Anne Jeffrey, Jonathan Martinez-Fabregas, Maximillian Hafer, Paul K. Fyfe, et al.. Competitive binding of stats to receptor phospho-tyr motifs accounts for altered cytokine responses. eLife, 2021, eLife, 10, ⟨10.7554/eLife.66014⟩. ⟨hal-04423993⟩
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