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Caspase-10 is a negative regulator of caspase-8-mediated cell death with gene inductive properties

Horn, Sebastian

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Death ligands such as CD95L and TRAIL initiate the extrinsic apoptotic signalling cascade by activation of the death-inducing signalling complex (DISC). Upon ligand binding to the receptor, the adaptor protein FADD is subsequently recruited to the receptor, thereby allowing for further recruitment of caspase-8 and its negative regulator cFLIP. In addition to the well-known caspase-8-mediated cell death induction, DISC-induced gene expression via the activation of NF-κB ruled out to be an important signalling pathway. Even if the major key players in DISC signalling have been described, the molecular mechanisms in DISC formation remain to be elucidated. In addition, the function of some DISC-associated proteins is unknown to date. To this day, the role of caspase-10, a homologue of caspase-8, in DISC signalling remains unknown and is controversially discussed. In this study, we elucidated the function of caspase 10 in DISC-induced cell death signalling and unexpectedly observed anti-apoptotic features under endogenous protein conditions. In contrast to previous thoughts, our data reveal that caspase-10 negatively regulates caspase 8-mediated cell death signalling in the DISC by blocking the recruitment to the complex and thereby the activation of caspase-8. Furthermore, we demonstrate that caspase 10 functions independent of cFLIP for inhibition of caspase-8 activation in the DISC. In addition, we show that caspase-8 does not compete with other tandem DED proteins such as cFLIP or caspase-10 in binding via FADD to the receptor as current models suggest. By utilising CRISPR-Cas9 mediated homologous recombination, we generated caspase-8 knockout cell lines and were able to demonstrate that caspase-8 has to be placed upstream of both cFLIP and caspase-10 in the DISC. We found that even FADD association with the DISC was drastically reduced in the absence of caspase-8. Interestingly, reconstitution of wild type caspase-8 and its active site mutant rescued the phenotype, indicating that caspase-8 is indispensable for the formation and/or stability of the DISC independent from its enzymatic activity. Moreover, we identified caspase 10 to promote DISC-mediated NF-κB activation. Caspase-10 favours at least the degradation of IκBα upon DISC stimulation resulting in enhanced NF-κB activation and inflammatory gene expression. Therefore, our data are consistent with a model in which caspase-10 rewires DISC signalling to NF-κB activation and cell survival. As a consequence, caspase-10 and cFLIP co-ordinately regulate caspase-8-mediated cell death signalling whereas both proteins contrast in their ability to induce gene expression upon death receptor activation.

Item Type: Dissertation
Supervisor: Angel, Prof. Dr. Peter
Date of thesis defense: 27 June 2016
Date Deposited: 14 Jul 2016 05:56
Date: 2017
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
570 Life sciences
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