Intra- and interdimeric caspase-8 self-cleavage controls strength and timing of CD95-induced apoptosis

• Verfasst von: Kallenberger, Stefan M. [VerfasserIn]
• Verfasst von: Beaudouin, Joël [VerfasserIn]
• Verfasst von: Claus, Juliane [VerfasserIn]
• Verfasst von: Eils, Roland [VerfasserIn]
• Titel: Intra- and interdimeric caspase-8 self-cleavage controls strength and timing of CD95-induced apoptosis
• Verf.angabe: Stefan M. Kallenberger, Joël Beaudouin, Juliane Claus, Carmen Fischer, Peter K. Sorger, Stefan Legewie, and Roland Eils
• E-Jahr: 2014
• Jahr: 11 Mar 2014
• Umfang: ? S.
• Fussnoten: Gesehen am 06.08.2020
• Titel Quelle: Enthalten in: Science signaling
• Ort Quelle: Washington, DC [u.a.] : Assoc., 2008
• Jahr Quelle: 2014
• Band/Heft Quelle: 7(2014,316) Artikel-Nummer ra23, 33 Seiten
• ISSN Quelle: 1937-9145
• DOI: doi:10.1126/scisignal.2004738
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1726534685

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. - Dual modes of activation of caspase-8 enable precise control of apoptosis. - Dual modes of activation of caspase-8 enable precise control of apoptosis.