Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection
Proceedings of the National Academy of Sciences, 2018•National Acad Sciences
Cell death and inflammation are intimately linked during Yersinia infection. Pathogenic
Yersinia inhibits the MAP kinase TGFβ-activated kinase 1 (TAK1) via the effector YopJ,
thereby silencing cytokine expression while activating caspase-8–mediated cell death.
Here, using Yersinia pseudotuberculosis in corroboration with costimulation of
lipopolysaccharide and (5Z)-7-Oxozeaenol, a small-molecule inhibitor of TAK1, we show
that caspase-8 activation during TAK1 inhibition results in cleavage of both gasdermin D …
Yersinia inhibits the MAP kinase TGFβ-activated kinase 1 (TAK1) via the effector YopJ,
thereby silencing cytokine expression while activating caspase-8–mediated cell death.
Here, using Yersinia pseudotuberculosis in corroboration with costimulation of
lipopolysaccharide and (5Z)-7-Oxozeaenol, a small-molecule inhibitor of TAK1, we show
that caspase-8 activation during TAK1 inhibition results in cleavage of both gasdermin D …
Cell death and inflammation are intimately linked during Yersinia infection. Pathogenic Yersinia inhibits the MAP kinase TGFβ-activated kinase 1 (TAK1) via the effector YopJ, thereby silencing cytokine expression while activating caspase-8–mediated cell death. Here, using Yersinia pseudotuberculosis in corroboration with costimulation of lipopolysaccharide and (5Z)-7-Oxozeaenol, a small-molecule inhibitor of TAK1, we show that caspase-8 activation during TAK1 inhibition results in cleavage of both gasdermin D (GSDMD) and gasdermin E (GSDME) in murine macrophages, resulting in pyroptosis. Loss of GsdmD delays membrane rupture, reverting the cell-death morphology to apoptosis. We found that the Yersinia-driven IL-1 response arises from asynchrony of macrophage death during bulk infections in which two cellular populations are required to provide signal 1 and signal 2 for IL-1α/β release. Furthermore, we found that human macrophages are resistant to YopJ-mediated pyroptosis, with dampened IL-1β production. Our results uncover a form of caspase-8–mediated pyroptosis and suggest a hypothesis for the increased sensitivity of humans to Yersinia infection compared with the rodent reservoir.
National Acad Sciences