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Kalliara E.♦, Kardynska M.♦, Bagnall J.♦, Spiller David G.♦, Müller W.♦, Ruckerl D.♦, Śmieja J.♦, Biswas Subhra K.♦, Paszek P., Post-transcriptional regulatory feedback encodes JAK-STAT signal memory of interferon stimulation,
Frontiers in Immunology, ISSN: 1664-3224, DOI: 10.3389/fimmu.2022.947213, Vol.13, pp.947213-1-19, 2022Abstract: Immune cells fine tune their responses to infection and inflammatory cues. Here, using live-cell confocal microscopy and mathematical modelling, we investigate interferon-induced JAK-STAT signalling in innate immune macrophages. We demonstrate that transient exposure to IFN-γ stimulation induces a long-term desensitisation of STAT1 signalling and gene expression responses, revealing a dose- and time-dependent regulatory feedback that controls JAK-STAT responses upon re-exposure to stimulus. We show that IFN-α/β1 elicit different level of desensitisation from IFN-γ, where cells refractory to IFN-α/β1 are sensitive to IFN-γ, but not vice versa. We experimentally demonstrate that the underlying feedback mechanism involves regulation of STAT1 phosphorylation but is independent of new mRNA synthesis and cognate receptor expression. A new feedback model of the protein tyrosine phosphatase activity recapitulates experimental data and demonstrates JAK-STAT network’s ability to decode relative changes of dose, timing, and type of temporal interferon stimulation. These findings reveal that STAT desensitisation renders cells with signalling memory of type I and II interferon stimulation, which in the future may improve administration of interferon therapy. Keywords: JAK-STAT network, STAT1 kinetics, interferons, pathway desensitisation, mathematical modelling, signal memory, live-cell microscopy Affiliations:
Kalliara E. | - | other affiliation | Kardynska M. | - | other affiliation | Bagnall J. | - | other affiliation | Spiller David G. | - | other affiliation | Müller W. | - | other affiliation | Ruckerl D. | - | other affiliation | Śmieja J. | - | Silesian University of Technology (PL) | Biswas Subhra K. | - | other affiliation | Paszek P. | - | IPPT PAN |
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