Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores

Xing Liu, Zhibin Zhang, Jianbin Ruan, Youdong Pan, Venkat Giri Magupalli, Hao Wu & Judy Lieberman

Nature. 2016 Jul 6;535(7610)

Speaker: Yeh, Zheng-Wei (葉正偉)                              Time: 14:10~15:00, Oct. 05, 2016

Commentator:Liu, Hsiao-Sheng, PhD (劉校生教授)  Place: Room 601

Abstract:

Canonical and non-canonical inflammasomes activate inflammatory caspases, including caspase-1, mouse caspase-11, and human caspase-4/5, to trigger IL-1β maturation and secretion as well as pyroptosis, a lytic form of cell death which is critical for innate immune defenses against intracellular bacterial infection. Recent studies revealed that Gasdermin D (GSDMD) is a downstream effector of non-canonical inflammasomes mediated by caspase-11 and caspase-4/5. Intracellular LPS binds to caspase-11 and then caspase-11 is activated to cleave gasdermin D. The N-terminal fragment of cleaved Gasdermin D, termed GSDMD-NT, can trigger pyroptosis as well as IL-1β secretion. However, the mechanistic mechanism of how Gasdermin D executes pyroptosis is still unknown. In this study, the authors first showed that GSDMD-NT could form oligomers in the cell. Of note, GSDMD-NT oligomers were shown to localize to the plasma membrane through binding to phospholipids. Furthermore, biochemical and microscopic analyses showed that GSDMD-NT oligomers could bind to liposomes and cause pore formation on liposomes. Finally, GSDMD-NT oligomers showed the bacterial killing effect in vitro. Together, this work reveals mechanistic insights into GSDMD-mediated pyroptosis.

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