Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses
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 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 concentrationsmore »
- Authors:
-
[1];
[2];
[1];
[3];
[1];
[2];
[2];
[3];
[5];
[1]
- University of Dundee (United Kingdom)
- University of Leeds (United Kingdom)
- University of Osnabrück (Germany)
- University Lille (France)
- University of Leeds (United Kingdom); Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Publication Date:
- Research Org.:
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
- Sponsoring Org.:
- USDOE National Nuclear Security Administration (NNSA); Horizon 2020; Wellcome Trust; Engineering and Physical Sciences Research Council (EPSRC); University of Leeds; European Molecular Biology Organization (EMBO); German Research Foundation (DFG); National Heart, Lung, and Blood Institute
- OSTI Identifier:
- 1897423
- Report Number(s):
- LA-UR-21-21441
Journal ID: ISSN 2050-084X
- Grant/Contract Number:
- 89233218CNA000001; 714680; 202323/Z/16/Z; 1969354; 764698/ ERC-206-STG; 454-2017; SFB944; K22HL125593
- Resource Type:
- Accepted Manuscript
- Journal Name:
- eLife
- Additional Journal Information:
- Journal Volume: 10; Journal ID: ISSN 2050-084X
- Publisher:
- eLife Sciences Publications, Ltd.
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; computational biology; systems biology; immunology; inflammation; cytokines; SLE; STAATS; IL6; IL27; signaling
Citation Formats
Wilmes, Stephan, Jeffrey, Polly-Anne, Martinez-Fabregas, Jonathan, Hafer, Maximillian, Fyfe, Paul K., Pohler, Elizabeth, Gaggero, Silvia, López-García, Martín, Lythe, Grant, Taylor, Charles, Guerrier, Thomas, Launay, David, Mitra, Suman, Piehler, Jacob, Molina-París, Carmen, and Moraga, Ignacio. Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses. United States: N. p., 2021.
Web. doi:10.7554/elife.66014.
Wilmes, Stephan, Jeffrey, Polly-Anne, Martinez-Fabregas, Jonathan, Hafer, Maximillian, Fyfe, Paul K., Pohler, Elizabeth, Gaggero, Silvia, López-García, Martín, Lythe, Grant, Taylor, Charles, Guerrier, Thomas, Launay, David, Mitra, Suman, Piehler, Jacob, Molina-París, Carmen, & Moraga, Ignacio. Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses. United States. https://doi.org/10.7554/elife.66014
Wilmes, Stephan, Jeffrey, Polly-Anne, Martinez-Fabregas, Jonathan, Hafer, Maximillian, Fyfe, Paul K., Pohler, Elizabeth, Gaggero, Silvia, López-García, Martín, Lythe, Grant, Taylor, Charles, Guerrier, Thomas, Launay, David, Mitra, Suman, Piehler, Jacob, Molina-París, Carmen, and Moraga, Ignacio. Mon .
"Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses". United States. https://doi.org/10.7554/elife.66014. https://www.osti.gov/servlets/purl/1897423.
@article{osti_1897423,
title = {Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses},
author = {Wilmes, Stephan and Jeffrey, Polly-Anne and Martinez-Fabregas, Jonathan and Hafer, Maximillian and Fyfe, Paul K. and Pohler, Elizabeth and Gaggero, Silvia and López-García, Martín and Lythe, Grant and Taylor, Charles and Guerrier, Thomas and Launay, David and Mitra, Suman and Piehler, Jacob and Molina-París, Carmen and Moraga, Ignacio},
abstractNote = {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.},
doi = {10.7554/elife.66014},
journal = {eLife},
number = ,
volume = 10,
place = {United States},
year = {Mon Apr 19 00:00:00 EDT 2021},
month = {Mon Apr 19 00:00:00 EDT 2021}
}
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