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Enteropathogenic E. coli stimulates effector-driven rapid caspase-4 activation in human macrophages

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Title: Enteropathogenic E. coli stimulates effector-driven rapid caspase-4 activation in human macrophages
Authors: Goddard, P
Sanchez Garrido, J
Slater, S
Kalyan, M
Ruano Gallego, D
Marchès, O
Fernández, LÁ
Frankel, G
Shenoy, A
Item Type: Journal Article
Abstract: Microbial infections can stimulate the assembly of inflammasomes, which activate caspase-1. The gastrointestinal pathogen enteropathogenic Escherichia coli (EPEC) causes localized actin polymerization in host cells. Actin polymerization requires the binding of the bacterial adhesin intimin to Tir, which is delivered to host cells via a type 3 secretion system (T3SS). We show that EPEC induces T3SS-dependent rapid non-canonical NLRP3 inflammasome activation in human macrophages. Notably, caspase-4 activation by EPEC triggers pyroptosis and cytokine processing through the NLRP3-caspase-1 inflammasome. Mechanistically, caspase-4 activation requires the detection of LPS and EPEC-induced actin polymerization, either via Tir tyrosine phosphorylation and the phosphotyrosine-binding adaptor NCK or Tir and the NCK-mimicking effector TccP. An engineered E. coli K12 could reconstitute Tir-intimin signaling, which is necessary and sufficient for inflammasome activation, ruling out the involvement of other virulence factors. Our studies reveal a crosstalk between caspase-4 and caspase-1 that is cooperatively stimulated by LPS and effector-driven actin polymerization.
Issue Date: 23-Apr-2019
Date of Acceptance: 27-Mar-2019
URI: http://hdl.handle.net/10044/1/69744
DOI: https://dx.doi.org/10.1016/j.celrep.2019.03.100
ISSN: 2211-1247
Publisher: Elsevier
Start Page: 1008
End Page: 1017.e6
Journal / Book Title: Cell Reports
Volume: 27
Issue: 4
Copyright Statement: © 2019 The Author(s).This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: MR/P028225/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
NONCANONICAL INFLAMMASOME ACTIVATION
ACTIN PEDESTAL FORMATION
NF-KAPPA-B
NLRP3 INFLAMMASOME
BACTERIAL FLAGELLIN
HOST-DEFENSE
PROTEIN
TIR
SECRETION
EXPRESSION
Publication Status: Published
Online Publication Date: 2019-04-23
Appears in Collections:Department of Medicine (up to 2019)
Faculty of Natural Sciences



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