Enteropathogenic Escherichia coli Stimulates Effector-Driven Rapid Caspase-4 Activation in Human Macrophages.

Autor:	Goddard PJ; Department of Life Sciences, Medical Research Council Centre for Molecular Bacteriology & Infection, Imperial College London, London, UK; Department of Medicine, Medical Research Council Centre for Molecular Bacteriology & Infection, Imperial College London, London, UK., Sanchez-Garrido J; Department of Medicine, Medical Research Council Centre for Molecular Bacteriology & Infection, Imperial College London, London, UK., Slater SL; Department of Life Sciences, Medical Research Council Centre for Molecular Bacteriology & Infection, Imperial College London, London, UK., Kalyan M; Department of Medicine, Medical Research Council Centre for Molecular Bacteriology & Infection, Imperial College London, London, UK., Ruano-Gallego D; Department of Microbial Biotechnology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain., Marchès O; Department of Life Sciences, Medical Research Council Centre for Molecular Bacteriology & Infection, Imperial College London, London, UK., Fernández LÁ; Department of Microbial Biotechnology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain., Frankel G; Department of Life Sciences, Medical Research Council Centre for Molecular Bacteriology & Infection, Imperial College London, London, UK., Shenoy AR; Department of Medicine, Medical Research Council Centre for Molecular Bacteriology & Infection, Imperial College London, London, UK. Electronic address: a.shenoy@imperial.ac.uk.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2019 Apr 23; Vol. 27 (4), pp. 1008-1017.e6.
DOI:	10.1016/j.celrep.2019.03.100
Abstrakt:	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. (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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