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

eLife

Martín López-García¹  Grant Lythe¹  Polly-Anne Jeffrey¹  Carmen Molina-París²  Jacob Piehler³  Maximillian Hafer³  Charles Taylor⁴  Ignacio Moraga⁵  Stephan Wilmes⁵  Jonathan Martinez-Fabregas⁵  Elizabeth Pohler⁵  Paul K Fyfe⁵  David Launay⁶  Thomas Guerrier⁶  Suman Mitra⁷  Silvia Gaggero⁷ 

[1] Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, United Kingdom;Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds, United Kingdom;T-6 Theoretical Division, Los Alamos National Laboratory, Los Alamos, United States;Department of Biology and Centre of Cellular Nanoanalytics, University of Osnabrück, Osnabrück, Germany;Department of Statistics, School of Mathematics, University of Leeds, Leeds, United Kingdom;Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom;Univ. Lille, Univ. LilleInserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France;Université de Lille, INSERM UMR1277 CNRS UMR9020–CANTHER and Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France;

关键词: cytokines;    SLE;    STATs;    IL6;    IL27;    signaling;    Human;   

DOI  :  10.7554/eLife.66014

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY