Insights into versatile molecular death switch
The research team studied the biological roles of caspase-8 in cell cultures and mice. Kashkar’s group showed that the enzymatic activity of caspase-8 is required to inhibit pyroptosis. ‘We found out that the expression of inactive caspase-8 causes embryonic lethality and inflammatory tissue destruction. This could only be restored when necroptosis and pyroptosis were simultaneously blocked,’ Hamid Kashkar explains. The lack of caspase-8 enzymatic activity primarily causes necroptotic cell death. Interestingly, when necroptosis is blocked, the inactive caspase-8 serves as a protein scaffold for the formation of a signalling protein complex called inflammasome, which ultimately induces pyroptosis. ‘Microbial pathogens are heavily reliant on the fate of infected cells and have evolved a number of strategies to inhibit apoptosis and necroptosis,’ Hamid Kashkar adds.
The current study hypothesises that these strategies may have driven the counter-evolution of pyroptosis to secure cellular death as a host defence mechanism. The caspase-8-mediated switch between different modes of cell death adds a critical layer to the plasticity of cell death-induced immunity, which is increasingly involved in aging-associated disorders.