Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction.

Molecular Systems Biology
Frédérique KokUrsula Klingmüller

Abstract

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 ...Continue Reading

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Citations

Oct 2, 2020·PLoS Pathogens·Katharina RobichonUrsula Klingmüller
Feb 8, 2021·Current Opinion in Cell Biology·Yanfei Jiang, Nan Hao
May 25, 2021·Frontiers in Cellular and Infection Microbiology·Supriya V BhatTanya E S Dahms
Aug 9, 2021·Trends in Immunology·Laura C Van EyndhovenJurjen Tel
Oct 26, 2021·Frontiers in Immunology·Duncan KirbyAnton Zilman

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Methods Mentioned

BETA
biopsies
electrophoretic mobility shift
immunoprecipitations
immunoprecipitation
transfection
FCS
Protein Assay
co‐immunoprecipitation
PCR
Assay

Software Mentioned

Fiji
Geneious
blotIt
Findpatterns
W2H
R package dMod
R package blotIt
LightCycler480SW1
ImageQuant
GelInspector

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