The type III secretion system effector EspO of enterohaemorrhagic Escherichia coli inhibits apoptosis through an interaction with HAX-1
Author(s)
Type
Journal Article
Abstract
Many enteric pathogens employ a type III secretion system (T3SS) to translocate effector proteins directly into the host cell cytoplasm, where they subvert signalling pathways of the intestinal epithelium. Here, we report that the anti-apoptotic regulator HS1-associated protein X1 (HAX-1) is an interaction partner of the T3SS effectors EspO of enterohaemorrhagic Escherichia coli (EHEC) and Citrobacter rodentium, OspE of Shigella flexneri and Osp1STYM of Salmonella enterica serovar Typhimurium. EspO, OspE and Osp1STYM have previously been reported to interact with the focal adhesions protein integrin linked kinase (ILK). We found that EspO localizes both to the focal adhesions (ILK localisation) and mitochondria (HAX-1 localisation), and that increased expression of HAX-1 leads to enhanced mitochondrial localisation of EspO. Ectopic expression of EspO, OspE and Osp1STYM protects cells from apoptosis induced by staurosporine and tunicamycin. Depleting cells of HAX-1 indicates that the anti-apoptotic activity of EspO is HAX-1 dependent. Both HAX-1 and ILK were further confirmed as EspO1-interacting proteins during infection using T3SS-delivered EspO1. Using cell detachment as a proxy for cell death we confirmed that T3SS-delivered EspO1 could inhibit cell death induced during EPEC infection, to a similar extent as the anti-apoptotic effector NleH, or treatment with the pan caspase inhibitor z-VAD. In contrast, in cells lacking HAX-1, EspO1 was no longer able to protect against cell detachment, while NleH1 and z-VAD maintained their protective activity. Therefore, during both infection and ectopic expression EspO protects cells from cell death by interacting with HAX-1. These results suggest that despite the differences between EHEC, C. rodentium, Shigella and S. typhimurium infections, hijacking HAX-1 anti-apoptotic signalling is a common strategy to maintain the viability of infected cells.
Take Away
EspO homologues are found in EHEC, Shigella, S. typhimurium and some EPEC.
EspO homologues interact with HAX-1.
EspO protects infected cells from apoptosis.
EspO joins a growing list of T3SS effectors that manipulate cell death pathways.
Take Away
EspO homologues are found in EHEC, Shigella, S. typhimurium and some EPEC.
EspO homologues interact with HAX-1.
EspO protects infected cells from apoptosis.
EspO joins a growing list of T3SS effectors that manipulate cell death pathways.
Date Issued
2021-09-01
Date Acceptance
2021-05-17
Citation
Cellular Microbiology, 2021, 23 (9)
ISSN
1462-5814
Publisher
Wiley
Journal / Book Title
Cellular Microbiology
Volume
23
Issue
9
Copyright Statement
© 2021 The Authors. Cellular Microbiology published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/34021690
Subjects
ACTIVATION
CASPASE-9
Cell Biology
CELL-DEATH
CITROBACTER-RODENTIUM
FOCAL ADHESIONS
infection
INFECTION
INFLAMMATION
INTEGRIN-LINKED KINASE
Life Sciences & Biomedicine
mechanism of action
microbial-cell interaction
Microbiology
PROTEIN X-1
Science & Technology
virulence
XIAP
Publication Status
Published
Coverage Spatial
United States
Article Number
e13366
Date Publish Online
2021-05-22