Kok2020 - IFNalpha-induced signaling in Huh7.5 cells
<notes xmlns="http://www.sbml.org/sbml/level2/version4"> <body xmlns="http://www.w3.org/1999/xhtml"> <p>The proposed ODE model describes dynamics of IFNalpha-induced signaling in Huh7.5 cells for a time scale up to 32 hours after stimulation with IFNalpha. The model consists of an IFN receptor model, formation/degradation and cytoplasmic/nuclear shuttling of STAT1-homodimers, STAT1-STAT2-heterodimers and STAT1-STAT2-IRF9 (ISGF3) complexes. On top, formation of feedback proteins STAT1, STAT2, IRF9, USP18, SOCS1, SOCS3 and IRF2 and corresponding influences on IFNalpha signaling dynamics was incorporated. The model was calibrated by dose response and time course measurements over 32 hours as well as time courses for USP18 inhibition and overexpression experiments. As a special focus, the model is able to describe dose-dependent sensitization and desensitization of IFNalpha signaling in form of double treatment experiments at 0h and 24h.</p> </body> </notes>
- Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction.
- Kok F, Rosenblatt M, Teusel M, Nizharadze T, Gonçalves Magalhães V, Dächert C, Maiwald T, Vlasov A, Wäsch M, Tyufekchieva S, Hoffmann K, Damm G, Seehofer D, Boettler T, Binder M, Timmer J, Schilling M, Klingmüller U
- Molecular systems biology , 7/ 2020 , Volume 16 , Issue 7 , pages: e8955 , PubMed ID: 32696599
- Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Tightly interlinked feedback regulators control the dynamics of intracellular responses elicited by the activation of signal transduction pathways. Interferon alpha (IFNα) orchestrates antiviral responses in hepatocytes, yet mechanisms that define pathway sensitization in response to prestimulation with different IFNα doses remained unresolved. We establish, based on quantitative measurements obtained for the hepatoma cell line Huh7.5, an ordinary differential equation model for IFNα signal transduction that comprises the feedback regulators STAT1, STAT2, IRF9, USP18, SOCS1, SOCS3, and IRF2. The model-based analysis shows that, mediated by the signaling proteins STAT2 and IRF9, prestimulation with a low IFNα dose hypersensitizes the pathway. In contrast, prestimulation with a high dose of IFNα leads to a dose-dependent desensitization, mediated by the negative regulators USP18 and SOCS1 that act at the receptor. The analysis of basal protein abundance in primary human hepatocytes reveals high heterogeneity in patient-specific amounts of STAT1, STAT2, IRF9, and USP18. The mathematical modeling approach shows that the basal amount of USP18 determines patient-specific pathway desensitization, while the abundance of STAT2 predicts the patient-specific IFNα signal response.
|SBML_IFNa_Huh75.xml||SBML representation of IFN alpha signaling model||228.59 KB||Preview | Download|
- Model originally submitted by : Marcus Rosenblatt
- Submitted: 29-Jul-2020 12:21:38
- Last Modified: 29-Jul-2020 12:21:38
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