Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses
- University of Dundee, United Kingdom
- University of Leeds, United Kingdom
- University of Osnabrück, Germany
- Université de Lille, France
- Universität Osnabrück, Germany
Abstract
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 modelling 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 phosphorylation. 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.
Data availability
Python (version 3.7) codes for the ABC-SMC model selection and parameter inference can be found in the public repository "https://github.com/PollyJeffrey/Cytokine_modelling", along with the results of the analysis. Phospho-proteomic and proteomic datasets were uploaded to the Proteome Exchange platform with accession numbers PXD024657 and PXD024188 respectively. RNA-seq dataset was uploaded in the GSE database with accession number GSE164479.
Article and author information
Author details
Polly-Anne Jeffrey
Jonathan Martinez-Fabregas
Ignacio Moraga Gonzalez
Funding
Horizon 2020 Framework programme (714680)
- Stephan Wilmes
- Jonathan Martinez-Fabregas
- Paul K Fyfe
- Ignacio Moraga Gonzalez
Wellcome Trust (202323/Z/16/Z)
- Stephan Wilmes
- Ignacio Moraga Gonzalez
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Frederik Graw, Heidelberg University, Germany
Ethics
Human subjects: This study was authorized by the French Competent Authority dealing with Research on Human Biological Samples namely the French Ministry of Research. The Authorization number is ECH 19/04. all patients gave their written informed consent
Version history
- Received: December 22, 2020
- Accepted: April 18, 2021
- Accepted Manuscript published: April 19, 2021 (version 1)
- Version of Record published: May 5, 2021 (version 2)
Copyright
© 2021, Wilmes et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses
eLife 10:e66014.
https://doi.org/10.7554/eLife.66014
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