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

Wilmes, S.; Jeffrey, P.-A.; Martinez-Fabregas, J.; Hafer, M.; Fyfe, P. K.; Pohler, E.; Gaggero, S.; Lythe, G.; Launay, D.; Mitra, S.; Piehler, J.; Molina-Paris, C.; Moraga Gonzalez, I.

doi:10.1101/2021.01.08.425379

bioRxiv · 10.1101/2021.01.08.425379

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

Wilmes, S.·Jeffrey, P.-A.·Martinez-Fabregas, J.·Hafer, M.·Fyfe, P. K.·Pohler, E.·Gaggero, S.·Lythe, G.·Launay, D.·Mitra, S.·Piehler, J.·Molina-Paris, C.·Moraga Gonzalez, I.

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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-27R, as the main dynamical processes contributing to sustained pSTAT1 by IL-27. Mutation of Tyr613 on IL-27R 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.

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Wilmes, S., Jeffrey, P.-A., Martinez-Fabregas, J., Hafer, M., Fyfe, P. K., Pohler, E., Gaggero, S., Lythe, G., Launay, D., Mitra, S., Piehler, J., Molina-Paris, C., Moraga Gonzalez, I.. 2021-01-09. Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses in autoimmune disorders. https://doi.org/10.1101/2021.01.08.425379

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