Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction

Mol Syst Biol. 2020 Jul;16(7):e8955. doi: 10.15252/msb.20198955.


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.

Keywords: dynamic pathway modeling; feedback control; interferon; personalized treatment; signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Feedback, Physiological / drug effects*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Humans
  • Interferon Regulatory Factor-2 / genetics
  • Interferon Regulatory Factor-2 / metabolism
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / genetics
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / metabolism
  • Interferon-alpha / pharmacology*
  • Models, Theoretical
  • RNA, Small Interfering
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism*
  • STAT2 Transcription Factor / genetics
  • STAT2 Transcription Factor / metabolism*
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Software
  • Suppressor of Cytokine Signaling 1 Protein / genetics
  • Suppressor of Cytokine Signaling 1 Protein / metabolism
  • Suppressor of Cytokine Signaling 3 Protein / genetics
  • Suppressor of Cytokine Signaling 3 Protein / metabolism
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism


  • IRF2 protein, human
  • IRF9 protein, human
  • Interferon Regulatory Factor-2
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • Interferon-alpha
  • RNA, Small Interfering
  • SOCS1 protein, human
  • SOCS3 protein, human
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT2 Transcription Factor
  • STAT2 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • USP18 protein, human
  • Ubiquitin Thiolesterase