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Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival

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 regulate...

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Autores principales: Horn, Sebastian, Hughes, Michelle A., Schilling, Ramon, Sticht, Carsten, Tenev, Tencho, Ploesser, Michaela, Meier, Pascal, Sprick, Martin R., MacFarlane, Marion, Leverkus, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413585/
https://www.ncbi.nlm.nih.gov/pubmed/28445729
http://dx.doi.org/10.1016/j.celrep.2017.04.010
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author Horn, Sebastian
Hughes, Michelle A.
Schilling, Ramon
Sticht, Carsten
Tenev, Tencho
Ploesser, Michaela
Meier, Pascal
Sprick, Martin R.
MacFarlane, Marion
Leverkus, Martin
author_facet Horn, Sebastian
Hughes, Michelle A.
Schilling, Ramon
Sticht, Carsten
Tenev, Tencho
Ploesser, Michaela
Meier, Pascal
Sprick, Martin R.
MacFarlane, Marion
Leverkus, Martin
author_sort Horn, Sebastian
collection PubMed
description 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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spelling pubmed-54135852017-05-10 Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival Horn, Sebastian Hughes, Michelle A. Schilling, Ramon Sticht, Carsten Tenev, Tencho Ploesser, Michaela Meier, Pascal Sprick, Martin R. MacFarlane, Marion Leverkus, Martin Cell Rep Article 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. Cell Press 2017-04-25 /pmc/articles/PMC5413585/ /pubmed/28445729 http://dx.doi.org/10.1016/j.celrep.2017.04.010 Text en © 2017 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Horn, Sebastian
Hughes, Michelle A.
Schilling, Ramon
Sticht, Carsten
Tenev, Tencho
Ploesser, Michaela
Meier, Pascal
Sprick, Martin R.
MacFarlane, Marion
Leverkus, Martin
Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival
title Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival
title_full Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival
title_fullStr Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival
title_full_unstemmed Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival
title_short Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival
title_sort caspase-10 negatively regulates caspase-8-mediated cell death, switching the response to cd95l in favor of nf-κb activation and cell survival
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413585/
https://www.ncbi.nlm.nih.gov/pubmed/28445729
http://dx.doi.org/10.1016/j.celrep.2017.04.010
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