Erratum: EspL is a bacterial cysteine protease effector that cleaves RHIM proteins to block necroptosis and inflammation.
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Cell death signalling pathways contribute to tissue homeostasis and provide innate protection from infection. Adaptor proteins such as receptor-interacting serine/threonine-protein kinase 1 (RIPK1), receptor-interacting serine/threonine-protein kinase 3 (RIPK3), TIR-domain-containing adapter-inducing interferon-β (TRIF) and Z-DNA-binding protein 1 (ZBP1)/DNA-dependent activator of IFN-regulatory factors (DAI) that contain receptor-interacting protein (RIP) homotypic interaction motifs (RHIM) play a key role in cell death and inflammatory signalling1,2,3. RHIM-dependent interactions help drive a caspase-independent form of cell death termed necroptosis4,5. Here, we report that the bacterial pathogen enteropathogenic Escherichia coli (EPEC) uses the type III secretion system (T3SS) effector EspL to degrade the RHIM-containing proteins RIPK1, RIPK3, TRIF and ZBP1/DAI during infection. This requires a previously unrecognized tripartite cysteine protease motif in EspL (Cys47, His131, Asp153) that cleaves within the RHIM of these proteins. Bacterial infection and/or ectopic expression of EspL leads to rapid inactivation of RIPK1, RIPK3, TRIF and ZBP1/DAI and inhibition of tumour necrosis factor (TNF), lipopolysaccharide or polyinosinic:polycytidylic acid (poly(I:C))-induced necroptosis and inflammatory signalling. Furthermore, EPEC infection inhibits TNF-induced phosphorylation and plasma membrane localization of mixed lineage kinase domain-like pseudokinase (MLKL). In vivo, EspL cysteine protease activity contributes to persistent colonization of mice by the EPEC-like mouse pathogen Citrobacter rodentium. The activity of EspL defines a family of T3SS cysteine protease effectors found in a range of bacteria and reveals a mechanism by which gastrointestinal pathogens directly target RHIM-dependent inflammatory and necroptotic signalling pathways.
Date Issued
2017-02-13
Date Acceptance
2016-11-28
Citation
Nature Microbiology, 2017, 2
ISSN
2058-5276
Publisher
Nature Publishing Group
Journal / Book Title
Nature Microbiology
Volume
2
Copyright Statement
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. The final publication is available at https://dx.doi.org/10.1038/nmicrobiol.2017.24
Identifier
http://www.ncbi.nlm.nih.gov/pubmed/28191895
PII: nmicrobiol201724
Publication Status
Published
Coverage Spatial
England
Article Number
16258