Caspase-11 Cleaves Gasdermin D for Non-canonical Inflammasome Signalling

Overview

Journal Nature

Specialty Science

Date 2015 Sep 17

PMID 26375259

Citations 1814

Authors

Nobuhiko Kayagaki

Irma B Stowe

Bettina L Lee

Karen ORourke

Keith Anderson

Soren Warming

Trinna Cuellar

Benjamin Haley

Merone Roose-Girma

Qui T Phung

Peter S Liu

Jennie R Lill

Hong Li

Jiansheng Wu

Sarah Kummerfeld

Juan Zhang

Wyne P Lee

Scott J Snipas

Guy S Salvesen

Lucy X Morris

Linda Fitzgerald

Yafei Zhang

Edward M Bertram

Christopher C Goodnow

Vishva M Dixit

Affiliations

Soon will be listed here.

Abstract

Intracellular lipopolysaccharide from Gram-negative bacteria including Escherichia coli, Salmonella typhimurium, Shigella flexneri, and Burkholderia thailandensis activates mouse caspase-11, causing pyroptotic cell death, interleukin-1β processing, and lethal septic shock. How caspase-11 executes these downstream signalling events is largely unknown. Here we show that gasdermin D is essential for caspase-11-dependent pyroptosis and interleukin-1β maturation. A forward genetic screen with ethyl-N-nitrosourea-mutagenized mice links Gsdmd to the intracellular lipopolysaccharide response. Macrophages from Gsdmd(-/-) mice generated by gene targeting also exhibit defective pyroptosis and interleukin-1β secretion induced by cytoplasmic lipopolysaccharide or Gram-negative bacteria. In addition, Gsdmd(-/-) mice are protected from a lethal dose of lipopolysaccharide. Mechanistically, caspase-11 cleaves gasdermin D, and the resulting amino-terminal fragment promotes both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Our data identify gasdermin D as a critical target of caspase-11 and a key mediator of the host response against Gram-negative bacteria.

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