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Death Receptor-Mediated Apoptosis and Lymphocyte Homeostasis
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Lixin Zheng, Richard M. Siegel, Jagan R. Muppidi, Felicita Hornung, Michael J. Lenardo
Death effector domains (DED) are interesting protein-interaction domains involved in apoptosis pathways. We have previously showed that overexpression of DED domains of FADD or caspase 8 causes formation of death filaments, which is well correlated with cell death.118 The mechanism of DED-induced cell death is not clear. One explanation is that when DED is overexpressed in cells, the homophilic association of DED may cause aggregation, which activates endogenous caspase-8 and/or -10. However, this hypothesis does not hold in certain circumstances. For example, there is evidence that the expression of human DED in bacteria causes bacterial death. It is unlikely that caspase activation is occurring in this case because no caspase homologue exists in bacterial genomes. Another explanation is that many overexpressed molecules can cause generic toxicity to host cells and that over expression of DEDs is just a trivial example of this phenomenon. This seems not to be the case in mammalian cells. Our recent data suggests that in caspase 8-deficient Jurkat T cells, the prodomains of caspase-8 and -10, each containing two DEDs, can mediate CD95-triggered, FADD-dependent cell death. Moreover, this cell death process is not inhibitable by the pan-caspase inhibitors zVAD and BocD, or by specific caspase 8/10 inhibitors such as IETD, DEVD, and zAEVD. Nevertheless, the RIP is required for this DED-mediated death signaling (Zheng and Lenardo, unpublished data). The involvement of RIP in an alternative pathway of CD95-death signals has been reported recently (Fig. 4).119 This alternative caspase-independent pathway of CD95-induced death and its physiological relevance are now under study. The biological significance of this new pathway of cell death largely depends on the confirmation of the existence of natural isoforms of caspase-8 and -10 that only contain the DEDs. Until now, these isoforms have been only observed at the mRNA level. Further work should establish if there is an alternative pathway of death receptor-mediated apoptosis, perhaps mediated by the DED-containing prodomains of caspase-8 and -10.
Hesperetin upregulates Fas/FasL expression and potentiates the antitumor effect of 5-fluorouracil in rat model of hepatocellular carcinoma
Published in Egyptian Journal of Basic and Applied Sciences, 2020
Merna G. Aboismaiel, Mohamed El-Mesery, Amro El-Karef, Mamdouh M. El-Shishtawy
Up-regulation of caspase-8 can be attributed to oligomerization of the death receptor Fas in response to binding of FasL, which leads to recruitment of the adaptor molecule FADD. FADD then mediates the recruitment of the initiator caspases, procaspase-8/-10 through a DED resulting in the formation of DISC where the initiator caspases are cleaved forming active caspase-8/-10 [33]. Consequently, caspase-3 is activated either directly and/or through a crosstalk between the extrinsic death receptor pathway and the intrinsic mitochondrial pathway where caspase-8 activation mediates the cleavage of BH3 interacting domain (Bid) into truncated Bid (tBid) [34].