Kallenberger2014 - CD95L induced apoptosis initiated by caspase-8, wild-type HeLa cells (cis/trans-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:
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.
This model is hosted on BioModels Database and identified by: BIOMD0000000526 .
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models .
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.
-
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.
Submitter of this revision: Stefan Kallenberger
Modellers: Stefan Kallenberger
Metadata information
Connected external resources
SBGN view in Newt Editor
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
|||
| BIOMD0000000526_url.xml | SBML L2V4 representation of Kallenberger2014 - CD95L induced apoptosis initiated by caspase-8, wild-type HeLa cells (cis/trans-cis/trans variant) | 45.32 KB | Preview | Download |
Additional files |
|||
| BIOMD0000000526-biopax2.owl | Auto-generated BioPAX (Level 2) | 35.91 KB | Preview | Download |
| BIOMD0000000526-biopax3.owl | Auto-generated BioPAX (Level 3) | 56.55 KB | Preview | Download |
| BIOMD0000000526.m | Auto-generated Octave file | 9.08 KB | Preview | Download |
| BIOMD0000000526.pdf | Auto-generated PDF file | 248.43 KB | Preview | Download |
| BIOMD0000000526.png | Auto-generated Reaction graph (PNG) | 450.12 KB | Preview | Download |
| BIOMD0000000526.sci | Auto-generated Scilab file | 6.49 KB | Preview | Download |
| BIOMD0000000526.svg | Auto-generated Reaction graph (SVG) | 65.37 KB | Preview | Download |
| BIOMD0000000526.vcml | Auto-generated VCML file | 60.39 KB | Preview | Download |
| BIOMD0000000526.xpp | Auto-generated XPP file | 6.22 KB | Preview | Download |
| BIOMD0000000526_urn.xml | Auto-generated SBML file with URNs | 44.67 KB | Preview | Download |
- Model originally submitted by : Stefan Kallenberger
- Submitted: Mar 5, 2014 6:31:42 PM
- Last Modified: Feb 25, 2015 12:39:32 PM
Revisions
-
Version: 2
- Submitted on: Feb 25, 2015 12:39:32 PM
- Submitted by: Stefan Kallenberger
- With comment: Current version of Kallenberger2014 - CD95L induced apoptosis initiated by caspase-8, wild-type HeLa cells (cis/trans-cis/trans variant)
-
Version: 1
- Submitted on: Mar 5, 2014 6:31:42 PM
- Submitted by: Stefan Kallenberger
- With comment: Original import of Kallenberger2014_Caspase8_cistrans_cistrans_HeLawt
(*) You might be seeing discontinuous
revisions as only public revisions are displayed here. Any private revisions
of this model will only be shown to the submitter and their collaborators.
: Variable used inside SBML models
| Species | Initial Concentration/Amount |
|---|---|
| PrNES mCherry SBO:0000178 ; probe ; Red fluorescent protein drFP583 ; nuclear export signal |
1909.0 mol |
| p43 CASP8 and FADD-like apoptosis regulator |
0.0 mol |
| tBid BH3-interacting domain death agonist ; mitochondrial outer membrane permeabilization |
0.0 mol |
| p30 CASP8 |
0.0 mol |
| DISC death-inducing signaling complex |
0.0 mol |
| FADD FAS-associated death domain protein |
90.0 mol |
| DISCp55 CASP8 ; death-inducing signaling complex |
0.0 mol |
| p18 Caspase-8 |
0.0 mol |
| Reactions | Rate | Parameters |
|---|---|---|
| PrNES_mCherry => PrNES + mCherry; p43, p18, PrNES_mCherry, p43, p18 | kD374probe*PrNES_mCherry*(p43+p18)*cell | kD374probe = 0.00153710001025539 |
| DISCp55 => p43; DISCp55 | kD374*DISCp55*cell | kD374 = 6.44612643975149E-4 |
| Bid => tBid; p43, p18, Bid, p43, p18 | kBid*Bid*(p43+p18)*cell | kBid = 5.2134055139547E-4 |
| p30 => p18 + DISC; DISCp55, p30, p30, DISCp55 | kD374trans_p55*p30*(DISCp55+p30)*cell | kD374trans_p55 = 5.43518631342483E-4 |
| p43 => p18 + DISC; p43 | kD216*p43*cell | kD216 = 0.00639775937416746 |
| DISC => FADD; DISC | koff_FADD*DISC*cell | koff_FADD = 0.00130854998177646 |
| DISCp55 => p30; p43, DISCp55, p43 | kD216trans_p43*DISCp55*p43*cell | kD216trans_p43 = 5.29906975294056E-5 |
| p43 => p18 + DISC; DISCp55, p30, p43, DISCp55, p30 | kD216trans_p55*p43*(DISCp55+p30)*cell | kD216trans_p55 = 2.23246421372882E-4 |
| p43 => p18 + DISC; p43, p43 | kD216trans_p43*p43*p43*cell | kD216trans_p43 = 5.29906975294056E-5 |
(added: 14 Mar 2014, 12:55:25, updated: 14 Mar 2014, 12:55:25)