| 1. |
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, 2022 Abstract:
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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| 2. |
Kardynska M.♦, Smieja J.♦, Paszek P., Puszyński K.♦, Application of Sensitivity Analysis to Discover Potential Molecular Drug Targets,
International Journal of Molecular Sciences, ISSN: 1422-0067, DOI: 10.3390/ijms23126604, Vol.23, No.12, pp.6604-1-17, 2022Abstract:
Mathematical modeling of signaling pathways and regulatory networks has been supporting experimental research for some time now. Sensitivity analysis, aimed at finding model parameters whose changes yield significantly altered cellular responses, is an important part of modeling work. However, sensitivity methods are often directly transplanted from analysis of technical systems, and thus, they may not serve the purposes of analysis of biological systems. This paper presents a novel sensitivity analysis method that is particularly suited to the task of searching for potential molecular drug targets in signaling pathways. Using two sample models of pathways, p53/Mdm2 regulatory module and IFN- Keywords:
bioinformatics, chemotherapy, sensitivity analysis, molecular drug targets, systems biology Affiliations:
| Kardynska M. | - | other affiliation | | Smieja J. | - | other affiliation | | Paszek P. | - | IPPT PAN | | Puszyński K. | - | Silesian University of Technology (PL) |
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