Caspase-8 Serves Both Apoptotic and Nonapoptotic Roles

Abstract

Knockout of caspase-8, a cysteine protease that participates in the signaling for cell death by receptors of the TNF/nerve growth factor family, is lethal to mice in utero. To explore tissue-specific roles of this enzyme, we established its conditional knockout using the Cre/loxP recombination system. Consistent with its role in cell death induction, deletion of caspase-8 in hepatocytes protected them from Fas-induced caspase activation and death. However, application of the conditional knockout approach to investigate the cause of death of caspase-8 knockout embryos revealed that this enzyme also serves cellular functions that are nonapoptotic. Its deletion in endothelial cells resulted in degeneration of the yolk sac vasculature and embryonal death due to circulatory failure. Caspase-8 deletion in bone-marrow cells resulted in arrest of hemopoietic progenitor functioning, and in cells of the myelomonocytic lineage, its deletion led to arrest of differentiation into macrophages and to cell death. Thus, besides participating in cell death induction by receptors of the TNF/nerve growth factor family, caspase-8, apparently independently of these receptors, also mediates nonapoptotic and perhaps even antiapoptotic activities.

Caspase function in programmed cell death

“…81,82 This recruitment results in caspase-8 activation and cell death. 83,84 The loss of function of caspase-8 provides one of the clearest phenotypes to support its role in extrinsic pathway of cell death. casp8 KO mice are embryonic lethal around E12 with The apoptotic caspases S Kumar smaller embryos displaying impaired heart muscle development and an accumulation of erythrocytes in the abdomen and in blood vessels in the trunk.…”

Apoptosis in the development of the immune system

“…Genetic deletion of the death adaptor FADD and Caspase-8 in the T-cell lineage has demonstrated that these proteins are essential for death receptor-mediated apoptosis; however, such deficient cells exhibit normal sensitivity to a variety of intrinsic cell death stimuli including cytokine withdrawal and cytotoxic stress. [6][7][8] Death receptor signaling can be inhibited by FLICE-inhibitory proteins (FLIPs) that are recruited to the DISC blocking the activation and release of Caspase-8. In cells such as lymphocytes (known as type I cells), death receptor-mediated apoptosis is independent of the BCL-2 family as activation of Caspase-8 is sufficient to catalyze the activation of the downstream caspase cascade.…”

“…40 A conditional allele of Caspase-8 has yielded instructive in assessing the role of Caspase-8 in lymphocyte development and homeostasis. 7,8 Unexpectedly, inducible deletion of Caspase-8 during bone marrow development caused hematopoietic progenitor cells to lose their ability to differentiate into lymphoid and myeloid lineages and to repopulate lethally irradiated recipients. 7 However, T-cell lineage-specific deletion of Caspase-8 demonstrated that thymocyte development occurs normally in these mice.…”

“…7,8 Unexpectedly, inducible deletion of Caspase-8 during bone marrow development caused hematopoietic progenitor cells to lose their ability to differentiate into lymphoid and myeloid lineages and to repopulate lethally irradiated recipients. 7 However, T-cell lineage-specific deletion of Caspase-8 demonstrated that thymocyte development occurs normally in these mice. These cells were markedly resistant to cell death induced by anti-Fas treatment but exhibit normal sensitivity to death mediated by signaling through the TCR.…”

RGD-FasL Induces Apoptosis of Pituitary Adenoma Cells

“…Caspase-8 is the prototypical apoptosis initiator caspase downstream of TNF super-family death receptors. With substrates that include apoptosis-related effector caspases and pro-apoptotic Bcl-2 family members, active caspase-8 is capable of unleashing cascades of cellular events that can result in apoptosis (39). Indeed, caspase-8-deficient cells are resistant to death receptor-mediated cell death both in vitro and in vivo.…”