Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 46; pp. E10888 - E10897
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13.11.2018
• Series: PNAS Plus
• Subjects: Animals; Apoptosis; Apoptosis - physiology; Apoptosis Regulatory Proteins - metabolism; Bacterial Proteins - metabolism; Biological Sciences; Caspase 8 - metabolism; Caspase-8; Cell death; Cleavage; Cytokines; Cytology; Humans; IL-1β; Inflammation; Interleukin 1; Interleukin-1 - metabolism; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Macrophages; Macrophages - metabolism; MAP kinase; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - metabolism; Mice; Mice, Inbred C57BL; Morphology; Mortality; PNAS Plus; Pseudotuberculosis; Pyroptosis; Pyroptosis - physiology; TAK1 protein; Yersinia; Yersinia Infections - metabolism; Yersinia Infections - pathology; Yersinia pseudotuberculosis - metabolism; pyroptosis; caspase-8; gasdermin; TAK1; Yersinia
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1809548115

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 gas-dermin 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.