Cycloheximide can induce bax/bak dependent myeloid cell death independently of multiple BH3-only proteins

10.1371/journal.pone.0164003PLoS ONE1111e016400

Apoptosis in Trypanosomatids: Evolutionary and phylogenetic considerations

Programmed cell death (PCD) or apoptosis, an active process of cell death, plays a central role in normal tissue development and organogenesis, as well as in the pathogenesis of different diseases. Although it occurs in diverse cells and tissues under the influence of a remarkable variety of inducing agents, the resultant ultrastructural and biochemical changes are extremely monotonous, indicating the existence of a common biological mechanism underlying its occurrence. It is generally accepted that a developmental program leading to cell death cannot be advantageous to unicellular organisms and that PCD appeared in evolution to fulfill the organizational needs of multicellular life. However, the recent description of apoptotic death occurring in three different species of pathogenic kinetoplastids suggests that the evolutionary origin of PCD precedes the appearence of multicellular organisms. The present study proposes that a population of pathogenic Trypanosomatids is socially organized and that PCD is a prerequisite for this organization and for the fulfillment of the demands of a heteroxenic lifestyle. This proposal includes possible roles for PCD in the development of the parasite in the insect vector and/or in its mammalian host and suggests experimental strategies to localize the evolutionary origin of PCD within the kinetoplastids.<br>A morte celular programada (PCD) ou apoptose, um processo ativo de morte celular, desempenha um papel fundamental no desenvolvimento tecidual normal e na organogênese, assim como na patogênese de diferentes doenças. Embora este processo ocorra em uma gama variada de diferentes células e tecidos, sob a influência dos mais diversos agentes indutores, a resultante morfológica e bioquímica do processo é extremamente monótona, sugerindo que um mecanismo único opere em todas as situações. Era consensualmente aceito que um programa de morte programada não poderia ser vantajoso para organismos unicelulares e que a PCD teria surgido na evolução para servir às necessidades organizacionais dos seres multicelulares. No entanto, a descrição de PCD em três diferentes espécies de tripanosomatídeos patogênicos indica que a origem da PCD é anterior à da multicelularidade. A hipótese colocada neste trabalho é a de que uma população de tripanosomatídeos tem uma organização social e que esta é necessária ao cumprimento das exigências biológicas de um parasita heterôxênico. A proposta inclui possíveis papéis biológicos para a PCD no desenvolvimento do parasita no inseto vetor e/ou no hospedeiro mamífero e sugere abordagens experimentais para se localizar a origem evolutiva da PCD entre os cinetoplastídeos

Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming.

A current paradigm proposes that mitochondrial damage is a critical determinant of NLRP3 inflammasome activation. Here, we genetically assess whether mitochondrial signalling represents a unified mechanism to explain how NLRP3 is activated by divergent stimuli. Neither co-deletion of the essential executioners of mitochondrial apoptosis BAK and BAX, nor removal of the mitochondrial permeability transition pore component cyclophilin D, nor loss of the mitophagy regulator Parkin, nor deficiency in MAVS affects NLRP3 inflammasome function. In contrast, caspase-8, a caspase essential for death-receptor-mediated apoptosis, is required for efficient Toll-like-receptor-induced inflammasome priming and cytokine production. Collectively, these results demonstrate that mitochondrial apoptosis is not required for NLRP3 activation, and highlight an important non-apoptotic role for caspase-8 in regulating inflammasome activation and pro-inflammatory cytokine levels

IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis.

XIAP prevents apoptosis by binding to and inhibiting caspases, and this inhibition can be relieved by IAP antagonists, such as Smac/DIABLO. IAP antagonist compounds (IACs) have therefore been designed to inhibit XIAP to kill tumor cells. Because XIAP inhibits postmitochondrial caspases, caspase 8 inhibitors should not block killing by IACs. Instead, we show that apoptosis caused by an IAC is blocked by the caspase 8 inhibitor crmA and that IAP antagonists activate NF-kappaB signaling via inhibtion of cIAP1. In sensitive tumor lines, IAP antagonist induced NF-kappaB-stimulated production of TNFalpha that killed cells in an autocrine fashion. Inhibition of NF-kappaB reduced TNFalpha production, and blocking NF-kappaB activation or TNFalpha allowed tumor cells to survive IAC-induced apoptosis. Cells treated with an IAC, or those in which cIAP1 was deleted, became sensitive to apoptosis induced by exogenous TNFalpha, suggesting novel uses of these compounds in treating cancer

A link between the antioxidant defense system and calcium: A proposal for the biochemical function of Bcl-2.

Tumorigenesis has long been viewed as a problem of perturbed regulation of cell proliferation. It has, however, become increasingly apparent during the last years that disturbance of the equilibrium between cell survival and cell death may equally contribute to the development of a tumor. Elimination of cells has first been described by morphologists as an important physiological process in developmental biology for which the term programmed cell death (PCD) or apoptosis has been coined, and has since then been recognized as a generally important phenomenon in many different areas of biology (Wyllie et al., 1980). Apart from morphological criteria, apoptosis is only poorly defined and discrimination from other forms of cell death is often difficult. Regardless of the definition of apoptosis, it is apparent that susceptibility versus resistance to toxic conditions or death inducing signals is an extremely important property of a cell determining its fate in its environmental context. &nbsp; &nbsp