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

Stephan Wilmes, Polly-Anne Jeffrey, Jonathan Martinez-Fabregas, Maximillian Hafer, Paul K. Fyfe, Elizabeth Pohler, Silvia Gaggero, Martin Lopez-Garcia, Grant Lythe, Charles Taylor, Thomas Guerrier, David Launay, Suman Mitra, Jacob Piehler, Carmen Molina-Paris (Lead / Corresponding author), Ignacio Moraga Gonzalez (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

3 Downloads (Pure)

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-27Ra, as the main dynamical processes contributing to sustained pSTAT1 levels by IL-27. Mutation of Tyr613 on IL-27Ra 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 IL6/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.

Original languageEnglish
Article numbere66014
Number of pages44
JournaleLife
Volume10
Early online date19 Apr 2021
DOIs
Publication statusPublished - 5 May 2021

Fingerprint

Dive into the research topics of 'Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses'. Together they form a unique fingerprint.

Cite this