Caspase-10 negatively regulates Caspase-8-Mediated cell death, switching the response to CD95L in favor of NF-[kappa]B activation and cell survival
Summary: Formation of the death-inducing signaling complex (DISC) initiates extrinsic apoptosis. Caspase-8 and its regulator cFLIP control death signaling by binding to death-receptor-bound FADD. By elucidating the function of the caspase-8 homolog, caspase-10, we discover that caspase-10 negatively...
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| Main Authors: | , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
April 25, 2017
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| In: |
Cell reports
Year: 2017, Volume: 19, Issue: 4, Pages: 785-797 |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2017.04.010 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1016/j.celrep.2017.04.010 Verlag, kostenfrei, Volltext: http://www.sciencedirect.com/science/article/pii/S2211124717304850 
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| Author Notes: | Sebastian Horn, Michelle A. Hughes, Ramon Schilling, Carsten Sticht, Tencho Tenev, Michaela Ploesser, Pascal Meier, Martin R. Sprick, Marion MacFarlane, and Martin Leverkus |
| Summary: | Summary: Formation of the death-inducing signaling complex (DISC) initiates extrinsic apoptosis. Caspase-8 and its regulator cFLIP control death signaling by binding to death-receptor-bound FADD. By elucidating the function of the caspase-8 homolog, caspase-10, we discover that caspase-10 negatively regulates caspase-8-mediated cell death. Significantly, we reveal that caspase-10 reduces DISC association and activation of caspase-8. Furthermore, we extend our co-operative/hierarchical binding model of caspase-8/cFLIP and show that caspase-10 does not compete with caspase-8 for binding to FADD. Utilizing caspase-8-knockout cells, we demonstrate that caspase-8 is required upstream of both cFLIP and caspase-10 and that DISC formation critically depends on the scaffold function of caspase-8. We establish that caspase-10 rewires DISC signaling to NF-κB activation/cell survival and demonstrate that the catalytic activity of caspase-10, and caspase-8, is redundant in gene induction. Thus, our data are consistent with a model in which both caspase-10 and cFLIP coordinately regulate CD95L-mediated signaling for death or survival. |
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| Item Description: | Gesehen am 04.09.2018 |
| Physical Description: | Online Resource |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2017.04.010 |