Insights into a versatile molecular death switch
The enzyme caspase-8 regulates different modes of cell death
CECAD
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 necropto¬¬sis 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.
Original publication
Melanie Fritsch, Saskia D. Günther, Robin Schwarzer, Marie-Christine Albert, Fabian Schorn, J. Paul Werthenbach, Lars M. Schiffmann, Neil Stair, Hannah Stocks, Jens M. Seeger, Mohamed Lamkanfi, Martin Krönke, Manolis Pasparakis & Hamid Kashkar; "Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis"; Nature; 2019
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Original publication
Melanie Fritsch, Saskia D. Günther, Robin Schwarzer, Marie-Christine Albert, Fabian Schorn, J. Paul Werthenbach, Lars M. Schiffmann, Neil Stair, Hannah Stocks, Jens M. Seeger, Mohamed Lamkanfi, Martin Krönke, Manolis Pasparakis & Hamid Kashkar; "Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis"; Nature; 2019
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