Non-canonical activation of Caspase 8 mediates pyroptosis

Abstract

Abstract Cell death and inflammation are intimately linked during homeostasis, host defense, and tumorigenesis. 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. The ensuing cell death is rapid and morphologically is similar to pyroptosis. Loss of GsdmD delays membrane rupture, reverting the cell-death morphology to apoptosis. The IL1 response arises from asynchrony of macrophage death during bulk infections in which two cellular populations provide signal 1 for transcriptional upregulation and signal 2 for the inflammasome assembly. 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. Altogether, this knowledge will be fundamental for our understanding of the mechanism of regulation of cell death and the discovery of new drug targets that can span areas from infections to tissue injury both in and ex vivo. This work was supported by the NIH grant AI056234 and Russian Science Foundation Grant 15-15-00100 (to A.P.)