Clustering of Tir during enteropathogenic E. coli infection triggers calcium influx–dependent pyroptosis in intestinal epithelial cells

Qiyun Zhong, Theodoros I Roumeliotis, Zuza Kozik, Massiel Cepeda-Molero, Luis Ángel Fernández, Avinash R Shenoy, Chris Bakal, Gad Frankel and Jyoti S Choudhary

PLOS Biology, 2020, vol. 18, issue 12, 1-31

Abstract: Clustering of the enteropathogenic Escherichia coli (EPEC) type III secretion system (T3SS) effector translocated intimin receptor (Tir) by intimin leads to actin polymerisation and pyroptotic cell death in macrophages. The effect of Tir clustering on the viability of EPEC-infected intestinal epithelial cells (IECs) is unknown. We show that EPEC induces pyroptosis in IECs in a Tir-dependent but actin polymerisation-independent manner, which was enhanced by priming with interferon gamma (IFNγ). Mechanistically, Tir clustering triggers rapid Ca2+ influx, which induces lipopolysaccharide (LPS) internalisation, followed by activation of caspase-4 and pyroptosis. Knockdown of caspase-4 or gasdermin D (GSDMD), translocation of NleF, which blocks caspase-4 or chelation of extracellular Ca2+, inhibited EPEC-induced cell death. IEC lines with low endogenous abundance of GSDMD were resistant to Tir-induced cell death. Conversely, ATP-induced extracellular Ca2+ influx enhanced cell death, which confirmed the key regulatory role of Ca2+ in EPEC-induced pyroptosis. We reveal a novel mechanism through which infection with an extracellular pathogen leads to pyroptosis in IECs.This study reveals a novel mechanism by which infection with enteropathogenic E. coli (EPEC) leads to pyroptosis in intestinal epithelial cells; this process is dependent on the type III secretion system effector Tir, and enhanced by priming with IFNγ. Intimin-mediated Tir clustering induces rapid calcium influx, which leads to internalisation of lipopolysaccharide, activation of caspase-4 and cleavage of gasdermin D.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pbio00:3000986

DOI: 10.1371/journal.pbio.3000986

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