1. EspL is a bacterial cysteine protease effector that cleaves RHIM proteins to block necroptosis and inflammation.
- Author
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Pearson JS, Giogha C, Mühlen S, Nachbur U, Pham CL, Zhang Y, Hildebrand JM, Oates CV, Lung TW, Ingle D, Dagley LF, Bankovacki A, Petrie EJ, Schroeder GN, Crepin VF, Frankel G, Masters SL, Vince J, Murphy JM, Sunde M, Webb AI, Silke J, and Hartland EL
- Subjects
- Animals, Cell Death, Citrobacter rodentium pathogenicity, Cysteine Proteases metabolism, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Enteropathogenic Escherichia coli enzymology, Enteropathogenic Escherichia coli metabolism, Escherichia coli Proteins genetics, HEK293 Cells, Humans, Lipopolysaccharides pharmacology, Mice, Phosphorylation, Receptor-Interacting Protein Serine-Threonine Kinases genetics, Signal Transduction drug effects, Tumor Necrosis Factor-alpha metabolism, Type III Secretion Systems, Apoptosis, Escherichia coli Proteins metabolism, Inflammation, Necrosis, Receptor-Interacting Protein Serine-Threonine Kinases metabolism
- 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 signalling
1-3 . 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.- Published
- 2017
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