Clustering of Tir During Enteropathogenic E. Coli Infection Triggers Calcium Influx-dependent Pyroptosis in Intestinal Epithelial Cells

Overview

Journal PLoS Biol

Specialty Biology

Date 2020 Dec 30

PMID 33378358

Citations 13

Authors

Qiyun Zhong

Theodoros I Roumeliotis

Zuza Kozik

Massiel Cepeda-Molero

Luis Angel Fernandez

Avinash R Shenoy

Chris Bakal

Gad Frankel

Jyoti S Choudhary

Affiliations

Soon will be listed here.

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.

Citing Articles

Sodium Butyrate Inhibits Necroptosis by Regulating MLKL via E2F1 in Intestinal Epithelial Cells of Liver Cirrhosis.

Zhou Y, Ding Y, Li Y, Sheng Q, Han C, Fan Y J Clin Transl Hepatol. 2025; 13(2):105-117.

PMID: 39917471 PMC: 11797820. DOI: 10.14218/JCTH.2024.00221.

Advances in research on the impact and mechanisms of pathogenic microorganism infections on pyroptosis.

Shang P, Gan M, Wei Z, Hu S, Song L, Feng J Front Microbiol. 2024; 15:1503130.

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Miner M, Rauch I Infect Immun. 2024; 92(9):e0048923.

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The pathogen-encoded signalling receptor Tir exploits host-like intrinsic disorder for infection.

Vieira M, Hernandez G, Zhong Q, Arbesu M, Veloso T, Gomes T Commun Biol. 2024; 7(1):179.

PMID: 38351154 PMC: 10864410. DOI: 10.1038/s42003-024-05856-9.

The role of TRPV4 in programmed cell deaths.

Ma Q, Wu J, Li H, Ma X, Yin R, Bai L Mol Biol Rep. 2024; 51(1):248.

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