Kok2020 - IFNalpha-induced signaling in Huh7.5 cells

Model Identifier
BIOMD0000000959
Short description
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.
Format
SBML
(L2V4)
Related Publication
-
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.
Contributors
Submitter of the first revision: Marcus Rosenblatt
Submitter of this revision: Krishna Kumar Tiwari
Modellers: Krishna Kumar Tiwari, Marcus Rosenblatt
Submitter of this revision: Krishna Kumar Tiwari
Modellers: Krishna Kumar Tiwari, Marcus Rosenblatt
Metadata information
is (3 statements)
isDescribedBy (1 statement)
hasProperty (3 statements)
occursIn (1 statement)
BioModels Database
MODEL2005110001
BioModels Database BIOMD0000000959
BioModels Database MODEL2005110001
BioModels Database BIOMD0000000959
BioModels Database MODEL2005110001
isDescribedBy (1 statement)
hasProperty (3 statements)
Mathematical Modelling Ontology
Ordinary differential equation model
Taxonomy Homo sapiens
Gene Ontology regulation of type I interferon-mediated signaling pathway
Taxonomy Homo sapiens
Gene Ontology regulation of type I interferon-mediated signaling pathway
occursIn (1 statement)
Curation status
Curated
Modelling approach(es)
Tags
Connected external resources
Name | Description | Size | Actions |
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Model files |
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Kok2020.xml | SBML L2V4 representation of IFNa signalling model | 271.56 KB | Preview | Download |
Additional files |
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Kok2020.cps | COPASI 4.29 (Build228) model file for the model | 308.41 KB | Preview | Download |
Kok2020.sedml | SEDML file for the model | 56.80 KB | Preview | Download |
SBML_IFNa_Huh75 (1).xml | Original xml file submitted by author | 228.59 KB | Preview | Download |
- Model originally submitted by : Marcus Rosenblatt
- Submitted: Jul 29, 2020 12:21:38 PM
- Last Modified: Aug 17, 2020 7:03:50 PM
Revisions
-
Version: 8
- Submitted on: Aug 17, 2020 7:03:50 PM
- Submitted by: Krishna Kumar Tiwari
- With comment: Automatically added model identifier BIOMD0000000959
-
Version: 6
- Submitted on: Jul 29, 2020 12:21:38 PM
- Submitted by: Krishna Kumar Tiwari
- With comment: Updated authors list for the submitted model
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revisions as only public revisions are displayed here. Any private revisions
of this model will only be shown to the submitter and their collaborators.
Legends
: Variable used inside SBML models
: Variable used inside SBML models
Species
Species | Initial Concentration/Amount |
---|---|
USP18 Q9UMW8 |
1746.0 nmol |
STAT2n P52630 ; Nuclear |
3039.0 nmol |
SOCS1mRNA Messenger RNA ; Suppressor of cytokine signaling 1 |
0.8286 nmol |
STAT1 LC 2 Signal transducer and activator of transcription 1-alpha/beta ; Translation ; Signal transducer and activator of transcription 1-alpha/beta |
460600.0 nmol |
STAT1 LC 3 Signal transducer and activator of transcription 1-alpha/beta ; Translation ; Signal transducer and activator of transcription 1-alpha/beta |
460600.0 nmol |
STAT2 LC 2 P52630 ; Translation ; P52630 |
2520.0 nmol |
USP18 LC 1 Q9UMW8 ; Translation ; Q9UMW8 |
1745.0 nmol |
STAT2c P52630 ; C13226 |
30390.0 nmol |
SOCS3mRNA Messenger RNA ; Suppressor of cytokine signaling 3 |
1.081 nmol |
STAT2 LC 5 P52630 ; Translation ; P52630 |
2520.0 nmol |
Reactions
Reactions | Rate | Parameters |
---|---|---|
USP18 => | compartment*k1*USP18 | k1=0.6719 |
STAT2n => STAT2c | compartment*k1*STAT2n | k1=1.81 |
=> SOCS1mRNA | compartment*v | v=1.301 |
STAT1_LC_1 => STAT1_LC_2 | compartment*k1*STAT1_LC_1 | k1=0.5275 |
STAT1_LC_2 => STAT1_LC_3 | compartment*k1*STAT1_LC_2 | k1=0.5275 |
STAT2_LC_2 => STAT2_LC_3 | compartment*k1*STAT2_LC_2 | k1=1.77 |
=> USP18_LC_1; USP18mRNA | compartment*synthUSP18*USP18mRNA | synthUSP18=1658.0 |
=> SOCS3mRNA; OccGASbs | compartment*synthSOCS3mRNA*OccGASbs | synthSOCS3mRNA=0.01205 |
STAT2_LC_5 => STAT2c | compartment*k1*STAT2_LC_5 | k1=1.77 |
Curator's comment:
(added: 17 Aug 2020, 19:03:35, updated: 17 Aug 2020, 19:03:35)
(added: 17 Aug 2020, 19:03:35, updated: 17 Aug 2020, 19:03:35)
Model simulated using copasi 4.29(build288) and results plotted using microsoft excel. Model reproduced figure 3A and 3b all simulation results. For IFNa stimulation of 0, 2.8, 28 and 1400 pM , extrapolated IFNa values taken were 100, 1000, 50000 respectively.