Pyroptosis is a highly inflammatory form of cell death that drives host protection against intracellular pathogens. Pyroptosis is initiated by inflammasome-activated inflammatory caspases (e.g. caspase-1/4/5/11), which cleave gasdermin D to trigger plasma membrane pores. In contrast, apoptosis is driven by apoptotic caspases (e.g. caspase-3/7/8/9), and is traditionally classified as an immunologically silent form of cell death that is important for development and maintenance of homeostasis. However, emerging studies suggest that caspase-8 activation during extrinsic apoptosis promotes inflammation by triggering the assembly of a proinflammatory, multi-protein complex called the NLRP3 inflammasome, through an ill-defined mechanism. A recent study identified a caspase-3 cleavage site within gasdermin D; cleavage of gasdermin D by apoptotic caspase-3 suppresses the cytotoxic function of this protein. These suggest a complex crosstalk between the pyroptosis and apoptosis. Therefore, the aim of this project is to investigate 1) novel proinflammatory functions of gasdermin D during extrinsic apoptosis; 2) the role of gasdermin D in caspase-8-dependent NLRP3 activation; and 3) the importance of caspase-3-mediated gasdermin D inactivation at steady state in vivo and during chemotherapy. This project will greatly enhance the skills and competence of the experienced researcher through advanced training and international mobility, and is in line with Horizon 2020 Work Programme objective.
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