Kallenberger2014 - CD95L induced apoptosis initiated by caspase-8, wild-type HeLa cells (cis/trans variant)

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Model Identifier
BIOMD0000000524
Short description
Kallenberger2014 - CD95L induced apoptosis initiated by caspase-8, wild-type HeLa cells (cis/trans variant)

The paper describes a new approach that combines single cell and population data in the same model. The model consists of a large number of single cell models, which are fitted to single cell data. Simultaneously, ensemble averages are fitted to population data. It is assumed that the kinetics in each cell can be described with the same kinetic parameters. Therefore, cell-to-cell variability is explained by variable initial protein concentrations.

There are four variants of the model (with [CD95L]=500ng/ml = 16.6nM), i) cistrans (in CD95-HeLa cells) [ MODEL1403050000 ], ii) cistrans (in wild-type HeLa cells) [ MODEL1403050001 ], iii) cistrans-cistrans (in CD95-HeLa cells) [ MODEL1403050002 ], and iv) cistrans-cistrans (in wild-type HeLa cells) [ MODEL1403050003 ].

These model contain the equations for one "average cell" with median initial concentrations for CD95, FADD, p55, BID, PrNES_mCherry and PrER_mGFP. By integrating the model, it should be possible to obtain trajectories for PrER_mGFP, PrNES_mCherry, p43 and p18 similar as in Figure 4A (CD95-HeLa cells) and Figure 4B (wild-type HeLa cells).

This model is described in the article:

Stefan M. Kallenberger, Joël Beaudouin, Juliane Claus, Carmen Fischer, Peter K. Sorger, Stefan Legewie, and Roland Eils
11 March 2014: Vol. 7, Issue 316, p. ra23

Abstract:

Apoptosis in response to the ligand CD95L (also known as Fas ligand) is initiated by caspase-8, which is activated by dimerization and self-cleavage at death-inducing signaling complexes (DISCs). Previous work indicated that the degree of substrate cleavage by caspase-8 determines whether a cell dies or survives in response to a death stimulus. To determine how a death ligand stimulus is effectively translated into caspase-8 activity, we assessed this activity over time in single cells with compartmentalized probes that are cleaved by caspase-8 and used multiscale modeling to simultaneously describe single-cell and population data with an ensemble of single-cell models. We derived and experimentally validated a minimal model in which cleavage of caspase-8 in the enzymatic domain occurs in an interdimeric manner through interaction between DISCs, whereas prodomain cleavage sites are cleaved in an intradimeric manner within DISCs. Modeling indicated that sustained membrane-bound caspase-8 activity is followed by transient cytosolic activity, which can be interpreted as a molecular timer mechanism reflected by a limited lifetime of active caspase-8. The activation of caspase-8 by combined intra- and interdimeric cleavage ensures weak signaling at low concentrations of CD95L and strongly accelerated activation at higher ligand concentrations, thereby contributing to precise control of apoptosis.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Format
SBML (L2V4)
Related Publication
  • Intra- and interdimeric caspase-8 self-cleavage controls strength and timing of CD95-induced apoptosis.
  • Kallenberger SM, Beaudouin J, Claus J, Fischer C, Sorger PK, Legewie S, Eils R
  • Science signaling , 3/ 2014 , Volume 7 , pages: ra23 , PubMed ID: 24619646
  • 1Department for Bioinformatics and Functional Genomics, Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg 69120, Germany.
  • Apoptosis in response to the ligand CD95L (also known as Fas ligand) is initiated by caspase-8, which is activated by dimerization and self-cleavage at death-inducing signaling complexes (DISCs). Previous work indicated that the degree of substrate cleavage by caspase-8 determines whether a cell dies or survives in response to a death stimulus. To determine how a death ligand stimulus is effectively translated into caspase-8 activity, we assessed this activity over time in single cells with compartmentalized probes that are cleaved by caspase-8 and used multiscale modeling to simultaneously describe single-cell and population data with an ensemble of single-cell models. We derived and experimentally validated a minimal model in which cleavage of caspase-8 in the enzymatic domain occurs in an interdimeric manner through interaction between DISCs, whereas prodomain cleavage sites are cleaved in an intradimeric manner within DISCs. Modeling indicated that sustained membrane-bound caspase-8 activity is followed by transient cytosolic activity, which can be interpreted as a molecular timer mechanism reflected by a limited lifetime of active caspase-8. The activation of caspase-8 by combined intra- and interdimeric cleavage ensures weak signaling at low concentrations of CD95L and strongly accelerated activation at higher ligand concentrations, thereby contributing to precise control of apoptosis.
Contributors
Stefan Kallenberger

Metadata information

is
BioModels Database MODEL1403050001
BioModels Database BIOMD0000000524
isDescribedBy
PubMed 24619646
hasTaxon
Taxonomy Homo sapiens
isVersionOf
Gene Ontology apoptotic process
hasProperty
Mathematical Modelling Ontology Ordinary differential equation model
occursIn
Brenda Tissue Ontology HeLa cell

Curation status
Curated


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Model files

BIOMD0000000524_url.xml SBML L2V4 representation of Kallenberger2014 - CD95L induced apoptosis initiated by caspase-8, wild-type HeLa cells (cis/trans variant) 38.10 KB Preview | Download

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BIOMD0000000524.png Auto-generated Reaction graph (PNG) 251.62 KB Preview | Download
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BIOMD0000000524_urn.xml Auto-generated SBML file with URNs 37.45 KB Preview | Download

  • Model originally submitted by : Stefan Kallenberger
  • Submitted: Mar 5, 2014 6:30:27 PM
  • Last Modified: Feb 25, 2015 12:37:11 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Feb 25, 2015 12:37:11 PM
    • Submitted by: Stefan Kallenberger
    • With comment: Current version of Kallenberger2014 - CD95L induced apoptosis initiated by caspase-8, wild-type HeLa cells (cis/trans variant)
  • Version: 1 public model Download this version
    • Submitted on: Mar 5, 2014 6:30:27 PM
    • Submitted by: Stefan Kallenberger
    • With comment: Original import of Kallenberger2014_Caspase8_cis_trans_HeLawt

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

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Species
Reactions
Reactions Rate Parameters
DISC => FADD; DISC koff_FADD*DISC*cell koff_FADD = 0.00566528253772301
Bid => tBid; p43, p18, Bid, p43, p18 kBid*Bid*(p43+p18)*cell kBid = 5.2867403363568E-4
PrER_mGFP => PrER + mGFP; p18, PrER_mGFP, p18 kD374probe*PrER_mGFP*p18*cell kD374probe = 0.00152252549827479
FADD => DISC; FADD kon_FADD*CD95act*FADD*cell kon_FADD = 8.11711012144556E-4; CD95act = 0.0
p55free + DISC => DISCp55; p55free, DISC kDISC*p55free*DISC*cell kDISC = 4.91828591049766E-4
p30 => p18 + DISC; DISCp55, p30, p30, DISCp55 kD374trans_p55*p30*(DISCp55+p30)*cell kD374trans_p55 = 4.46994772958953E-4
p30 => p18 + DISC; p43, p30, p43 kD374trans_p43*p30*p43*cell kD374trans_p43 = 0.00343995957326369
DISCp55 => p30; DISCp55 kD216*DISCp55*cell kD216 = 0.0114186392006403
DISCp55 => p43; p43, DISCp55, p43 kD374trans_p43*DISCp55*p43*cell kD374trans_p43 = 0.00343995957326369
p43 => p18 + DISC; p43 kD216*p43*cell kD216 = 0.0114186392006403
DISCp55 => p43; DISCp55, p30, DISCp55, p30 kD374trans_p55*DISCp55*(DISCp55+p30)*cell kD374trans_p55 = 4.46994772958953E-4
Curator's comment:
(added: 14 Mar 2014, 12:22:56, updated: 14 Mar 2014, 12:22:56)
This model contain the equations for one "average cell" with median initial concentrations for CD95, FADD, p55, BID, PrNES_mCherry and PrER_mGFP. Figure 4B in the reference publication gives the simulation and experimental results of several cells (80 different cells). As this model is a "average cell" model, trajectories similar to that of Figure 4B has been reproduced, but for the ligand concentration of 500ng/ml (CD95L = 16.6nM (500ng/ml)). The simulation results are checked with the authors. The model was simulated using Copasi v4.12 (Build 72). The plot was generated using Gnuplot.