Intra- and interdimeric caspase-8 self-cleavage controls strength and timing of CD95-induced apoptosis
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 die...
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| Main Authors: | , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
11 Mar 2014
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| In: |
Science signaling
Year: 2014, Volume: 7, Issue: 316 |
| ISSN: | 1937-9145 |
| DOI: | 10.1126/scisignal.2004738 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1126/scisignal.2004738 Verlag, lizenzpflichtig, Volltext: https://stke.sciencemag.org/content/7/316/ra23 Verlag, lizenzpflichtig, Volltext: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208692/pdf/nihms627852.pdf 
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| Author Notes: | Stefan M. Kallenberger, Joël Beaudouin, Juliane Claus, Carmen Fischer, Peter K. Sorger, Stefan Legewie, and Roland Eils |
| Summary: | 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. - Dual modes of activation of caspase-8 enable precise control of apoptosis. - Dual modes of activation of caspase-8 enable precise control of apoptosis. |
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| Item Description: | Gesehen am 06.08.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1937-9145 |
| DOI: | 10.1126/scisignal.2004738 |