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Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction

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...

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Autores principales: Kok, Frédérique, Rosenblatt, Marcus, Teusel, Melissa, Nizharadze, Tamar, Gonçalves Magalhães, Vladimir, Dächert, Christopher, Maiwald, Tim, Vlasov, Artyom, Wäsch, Marvin, Tyufekchieva, Silvana, Hoffmann, Katrin, Damm, Georg, Seehofer, Daniel, Boettler, Tobias, Binder, Marco, Timmer, Jens, Schilling, Marcel, Klingmüller, Ursula
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373899/
https://www.ncbi.nlm.nih.gov/pubmed/32696599
http://dx.doi.org/10.15252/msb.20198955
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author Kok, Frédérique
Rosenblatt, Marcus
Teusel, Melissa
Nizharadze, Tamar
Gonçalves Magalhães, Vladimir
Dächert, Christopher
Maiwald, Tim
Vlasov, Artyom
Wäsch, Marvin
Tyufekchieva, Silvana
Hoffmann, Katrin
Damm, Georg
Seehofer, Daniel
Boettler, Tobias
Binder, Marco
Timmer, Jens
Schilling, Marcel
Klingmüller, Ursula
author_facet Kok, Frédérique
Rosenblatt, Marcus
Teusel, Melissa
Nizharadze, Tamar
Gonçalves Magalhães, Vladimir
Dächert, Christopher
Maiwald, Tim
Vlasov, Artyom
Wäsch, Marvin
Tyufekchieva, Silvana
Hoffmann, Katrin
Damm, Georg
Seehofer, Daniel
Boettler, Tobias
Binder, Marco
Timmer, Jens
Schilling, Marcel
Klingmüller, Ursula
author_sort Kok, Frédérique
collection PubMed
description 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.
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spelling pubmed-73738992020-07-22 Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction Kok, Frédérique Rosenblatt, Marcus Teusel, Melissa Nizharadze, Tamar Gonçalves Magalhães, Vladimir Dächert, Christopher Maiwald, Tim Vlasov, Artyom Wäsch, Marvin Tyufekchieva, Silvana Hoffmann, Katrin Damm, Georg Seehofer, Daniel Boettler, Tobias Binder, Marco Timmer, Jens Schilling, Marcel Klingmüller, Ursula Mol Syst Biol Articles 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. John Wiley and Sons Inc. 2020-07-21 /pmc/articles/PMC7373899/ /pubmed/32696599 http://dx.doi.org/10.15252/msb.20198955 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Kok, Frédérique
Rosenblatt, Marcus
Teusel, Melissa
Nizharadze, Tamar
Gonçalves Magalhães, Vladimir
Dächert, Christopher
Maiwald, Tim
Vlasov, Artyom
Wäsch, Marvin
Tyufekchieva, Silvana
Hoffmann, Katrin
Damm, Georg
Seehofer, Daniel
Boettler, Tobias
Binder, Marco
Timmer, Jens
Schilling, Marcel
Klingmüller, Ursula
Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction
title Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction
title_full Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction
title_fullStr Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction
title_full_unstemmed Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction
title_short Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction
title_sort disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373899/
https://www.ncbi.nlm.nih.gov/pubmed/32696599
http://dx.doi.org/10.15252/msb.20198955
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