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Caspase-1 triggers programmed necrosis called pyroptosis by gasdermin-D (GSDMD) cleavage. GSDMD-deficient cells are, however, susceptible to caspase-1-mediated cell death. Researchers at Kanazawa University and others discovered that caspase-1 proteolytically activates Bid and initiates apoptosis in GSDMD-deficient cells. Furthermore, cortical neurons and mast cells, exhibiting little GSDMD expression, undergo apoptosis after appropriate stimulation in a caspase-1- and Bid-dependent manner. This study clarifies molecular mechanisms and biological roles of caspase-1-induced apoptosis in GSDMD-low/null cells.
Most unnecessary or dangerous cells, such as virus-infected cells, commit suicide by activating an in-built suicide program called apoptosis. This type of cell death is referred to as "programmed cell death." Until about year 2000, apoptosis was believed to be the sole mode of programmed cell death, at least in mammals. However, in recent years, various modes of "non-apoptotic" programmed cell death, called pyroptosis and necroptosis, have been defined based on the molecular mechanisms and morphological characteristics.
Process - Apoptosis - Group - Proteases - Caspases
In the process of apoptosis, the group of proteases called caspases, about 10 species of which are found in humans, function as suicide enzymes. Caspase-1, the first caspase found in mammals, has been reported to induce apoptosis in neurons in animal models of neurological disorders such as cerebral infarction, Alzheimer's disease and amyotrophic lateral sclerosis (ALS). However, subsequent studies revealed that in macrophages infected by bacteria, caspase-1 induces necrosis-like and inflammatory programmed cell death, which was thereafter named pyroptosis. Thus, caspase-1 has been reported to induce apoptosis or pyroptosis depending on the biological context (Figure 1). The reason for this apparent discrepancy has not been clarified.
Recently, it was revealed that pyroptosis is induced by proteolysis of a protein called gasdermin D (GSDMD) by caspase-1. Nonetheless, macrophages whose GSDMD gene was destroyed exhibited cell death upon activation of caspase-1, although more slowly than wild-type macrophages. Therefore, it seemed that there should be a mechanism...
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