Title :

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

Author(s) :

Wilmes, Stephan [Auteur]
University of Dundee
Jeffrey, Polly-Anne [Auteur]
University of Leeds
Martinez-Fabregas, Jonathan [Auteur]
University of Dundee
Hafer, Maximillian [Auteur]
Universität Osnabrück - Osnabrück University
Fyfe, Paul K. [Auteur]
University of Dundee
Pohler, Elizabeth [Auteur]
University of Dundee
Gaggero, Silvia [Auteur]
Miniaturisation pour la Synthèse, l'Analyse et la Protéomique (MSAP) - USR 3290
Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277
Lopez-Garcia, Martin [Auteur]
University of Leeds
Lythe, Grant [Auteur]
University of Leeds
Taylor, Charles [Auteur]
University of Leeds
Guerrier, Thomas [Auteur]
Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286
Launay, David [Auteur]
Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286
Mitra, Suman [Auteur]
Miniaturisation pour la Synthèse, l'Analyse et la Protéomique (MSAP) - USR 3290
Piehler, Jacob [Auteur]
Universität Osnabrück - Osnabrück University
Molina-Paris, Carmen [Auteur]
University of Leeds
Los Alamos National Laboratory [LANL]
Moraga Gonzalez, Ignacio [Auteur]
University of Dundee

Journal title :

eLife

Abbreviated title :

Elife

Volume number :

10

Publication date :

2021-04-19

ISSN :

2050-084X

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

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 ...
Show more >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.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

CHU Lille
CNRS
Inserm
Université de Lille

Collections :

• Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286
• Miniaturisation pour la Synthèse, l'Analyse et la Protéomique (MSAP) - USR 3290

Submission date :

2021-07-06T12:44:25Z
2024-01-29T12:56:39Z