Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis duringYersiniainfection

Author:

Sarhan Joseph,Liu Beiyun C.,Muendlein Hayley I.,Li Peng,Nilson Rachael,Tang Amy Y.,Rongvaux Anthony,Bunnell Stephen C.,Shao Feng,Green Douglas R.,Poltorak Alexander

Abstract

Cell death and inflammation are intimately linked duringYersiniainfection. PathogenicYersiniainhibits the MAP kinase TGFβ-activated kinase 1 (TAK1) via the effector YopJ, thereby silencing cytokine expression while activating caspase-8–mediated cell death. Here, usingYersinia pseudotuberculosisin 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 theYersinia-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 toYersiniainfection compared with the rodent reservoir.

Funder

NIH/NIAID

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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