EspL is a bacterial cysteine protease effector that cleaves RHIM proteins to block necroptosis and inflammation

Jaclyn S. Pearson, Cristina Giogha, Sabrina Mühlen, Ueli Nachbur, Chi L L Pham, Ying Zhang, Joanne M. Hildebrand, Clare V. Oates, Tania Wong Fok Lung, Danielle Ingle, Laura F. Dagley, Aleksandra Bankovacki, Emma J. Petrie, Gunnar N. Schroeder, Valerie F. Crepin, Gad Frankel, Seth L. Masters, James Vince, James M. Murphy, Margaret SundeAndrew I. Webb, John Silke, Elizabeth L. Hartland*

*Corresponding author for this work

Research output: Contribution to journalArticle

53 Citations (Scopus)
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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 necroptosis 4,5. 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.

Original languageEnglish
Article number16258
JournalNature Microbiology
Volume2
DOIs
Publication statusPublished - 13 Jan 2017
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Applied Microbiology and Biotechnology
  • Immunology
  • Microbiology (medical)
  • Cell Biology
  • Genetics

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    Pearson, J. S., Giogha, C., Mühlen, S., Nachbur, U., Pham, C. L. L., Zhang, Y., Hildebrand, J. M., Oates, C. V., Lung, T. W. F., Ingle, D., Dagley, L. F., Bankovacki, A., Petrie, E. J., Schroeder, G. N., Crepin, V. F., Frankel, G., Masters, S. L., Vince, J., Murphy, J. M., ... Hartland, E. L. (2017). EspL is a bacterial cysteine protease effector that cleaves RHIM proteins to block necroptosis and inflammation. Nature Microbiology, 2, [16258]. https://doi.org/10.1038/nmicrobiol.2016.258