The bacterial effectors EspG and EspG2 induce a destructive calpain activity that is kept in check by the co-delivered Tir effector

Dean, Paul; Mühlen, Sabrina; Quitard, Sabine; Kenny, Brendan

doi:10.1111/j.1462-5822.2010.01469.x

Cited by 28 publications

(26 citation statements)

References 55 publications

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“…Recent evidence suggests that the interaction of Intimin with the Tir effector (13) is a prerequisite event that is necessary for the TJ-disrupting activities of the other effectors, providing EPEC with additional control over effector function (13). This shows that EspF requires additional EPEC-mediated signaling to disrupt the TJs, and this is further supported by a separate study in which expression of EspF alone within epithelial cells had no observable effect on tight junctions (1).…”

Section: Espf-mediated Cellular Changes Linked Directly To Diarrheasupporting

confidence: 65%

“…This function was the first ascribed to EspF (35) and was also used to identify EspF's molecular chaperone CesF (16). The authors of the former study speculated that EspF may not be acting alone in the disruption of TJs (35), and indeed, subsequent studies have shown that EspF cooperates with the EPEC effectors Map, Tir, EspG, and NleA to mediate rapid TJ disruption (11,13,53,54). The molecular details of EspF-mediated TJ disruption are slowly becoming unraveled, and while mitochondrial targeting is not involved (58), the recruitment of tight junctional proteins to bacterium-induced pedestals by EspF has been implicated (45).…”

Section: Espf-mediated Cellular Changes Linked Directly To Diarrheamentioning

confidence: 99%

“…Although EPEC induces apoptosis in nonpolarized cell types, such as HeLa cells in vitro (9,40,42), the apoptotic index is quite low, particularly compared to that of other pathogens (8,13). In addition, target cell types such as polarized intestinal cells are relatively resistant to EPEC-mediated apoptosis (58), and late-stage apoptotic events are rarely observed for EPEC-infected cells (23).…”

Section: Role In Apoptosismentioning

confidence: 99%

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The EspF Effector, a Bacterial Pathogen's Swiss Army Knife

et al. 2010

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2Central to the pathogenesis of many bacterial pathogens is the ability to deliver effector proteins directly into the cells of their eukaryotic host. EspF is one of many effector proteins exclusive to the attaching and effacing pathogen family that includes enteropathogenic (EPEC) and enterohemorrhagic (EHEC) Escherichia coli. Work in recent years has revealed EspF to be one of the most multifunctional effector proteins known, with defined roles in several host cellular processes, including disruption of the epithelial barrier, antiphagocytosis, microvillus effacement, host membrane remodelling, modulation of the cytoskeleton, targeting and disruption of the nucleolus, intermediate filament disruption, cell invasion, mitochondrial dysfunction, apoptosis, and inhibition of several important epithelial transporters. Surprisingly, despite this high number of functions, EspF is a relatively small effector protein, and recent work has begun to decipher the molecular events that underlie its multifunctionality. This review focuses on the activities of EspF within the host cell and discusses recent findings and molecular insights relating to the virulence functions of this fascinating bacterial effector.

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Section: Espf-mediated Cellular Changes Linked Directly To Diarrheasupporting

confidence: 65%

Section: Espf-mediated Cellular Changes Linked Directly To Diarrheamentioning

confidence: 99%

Section: Role In Apoptosismentioning

confidence: 99%

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The EspF Effector, a Bacterial Pathogen's Swiss Army Knife

et al. 2010

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“…It has been reported that both EPEC and EHEC can induce rearrangements of the actin cytoskeleton [41]. The EPEC EspF protein collaborated with the effectors Map, Tir, EspG and NleA to interfere with TJs [42][43][44]. Moreover, EspF can cause actin sequestration and recruit junctional proteins, such as occludin, claudin, ZO-1 and ZO-2, to the pedestals, inducing the redistribution and loss of transepithelial electrical resistance, disruption of paracellular permeability and depolymerization of actin.…”

Section: Resultsmentioning

confidence: 99%

Screening for Host Proteins Interacting with Escherichia Coli O157:H7 EspF using Bimolecular Fluorescence Complementation

Hua

Wang

et al. 2017

Future Microbiol.

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Aim:To screen host proteins that interact with enterohemorrhagic Escherichia coli O157:H7 EspF. Materials & methods: Flow cytometry and high-throughput sequencing were used to screen interacting proteins. Molecular function, biological processes and Kyoto Encyclopedia of Genes and Genomes pathways were studied using the DAVID online tool. Glutathione S-transferase pull down and dot blotting were used to verify the interactions. Results: 293 host proteins were identified to associate with EspF. They were mainly enriched in RNA splicing (p = 0.005), ribosome structure (p = 0.012), and involved in 109 types of signaling pathways. SNX9 and ANXA6 were confirmed to interact with EspF. Conclusion: EspF interacts with ANXA6; they may form a complex to manipulate the process of phagocytosis; EspF plays a highlighted pathogenic role in enterohemorrhagic E. coli infection process. Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is an important food-borne causative agent in sporadic outbreaks of illness such as diarrhea, hemorrhagic colitis and hemolytic-uremic syndrome. Severe symptoms may even lead to death [1][2][3][4]. Research into EHEC has mainly explored the development of attaching and effacing (A/E) intestinal lesions and the secretion of Shiga toxin in EHEC infection [5][6][7]. The protein EspF is one of the multifunctional effectors of A/E lesions induced by EHEC and enteropathogenic E. coli (EPEC). EspF participates in a number of damage processes in host cells, targeting mitochondria and nucleoli [6,8] and disrupting the tight junctions (TJs) of intestinal epithelial cells [9], leading to cytoskeletal rearrangements, actin polymerization and pedestal formation [10]. EspF thus emerges as the 'Swiss army knife' of a bacterial pathogen [11,12]. EHEC O157:H7 employs a type-III secretion system to export toxic factors and effector proteins to host cells after adhering to the brush border of epithelial cells [5,[13][14]. The production of virulence factors, subsequent invasion and diffusion, and the interaction of effector proteins with host proteins are key steps in EHEC O157:H7 pathogenesis. The mechanism by which EspF breaks through the intestinal epithelial barrier into host cells, the host proteins that EspF interacts with, and how cellular damage, and even apoptosis, result remain unclear. Studying the pathogen-host interaction process will increase the emerging knowledge about EHEC O157:H7 pathogenesis.The EspF protein has been shown to induce apoptosis after 'injection' into host cells [1]. The N-terminal (1-73 amino acids [aa]) of this approximately 27 kDa protein contains a secretory signal (1-20 aa), a mitochondrialtargeting signal (1-24 aa) and a nucleolar-targeting domain (21-74 aa); 73-248 aa consists of four proline-rich repeats (PRRs), each containing a eukaryotic cell sorting nexin 9 (SNX9) protein-binding site SH3 motif, an

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“…tEPEC OMPs in fully differentiated Caco-2 cells monolayers induce changes in adherens junctions, leading to the dissociation of the cadherin/␤-catenin complex and the cytoplasmic redistribution of ␤-catenins through the activation of PKC-␣ signaling (689). In fully differentiated Caco-2 cells, EspG and EspG2, through their activation of the host cysteine protease calpain, lead to a loss of TER and a rapid cell loss and necrosis, a phenomenon that is increased in the absence of Tir (690). The EspG effector and its homologue Orf3 are both involved in microtubule disruption in fully differentiated Caco-2 cells, but EspG alone has no effect on TER, whereas EspG combined with Orf3 decreases TER (691).…”

Section: Structural and Functional Injuries At The Junctional Domainmentioning

confidence: 99%

Pathogenesis of Human Enterovirulent Bacteria: Lessons from Cultured, Fully Differentiated Human Colon Cancer Cell Lines

Moal

Servin

2013

Microbiol Mol Biol Rev

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SUMMARY Hosts are protected from attack by potentially harmful enteric microorganisms, viruses, and parasites by the polarized fully differentiated epithelial cells that make up the epithelium, providing a physical and functional barrier. Enterovirulent bacteria interact with the epithelial polarized cells lining the intestinal barrier, and some invade the cells. A better understanding of the cross talk between enterovirulent bacteria and the polarized intestinal cells has resulted in the identification of essential enterovirulent bacterial structures and virulence gene products playing pivotal roles in pathogenesis. Cultured animal cell lines and cultured human nonintestinal, undifferentiated epithelial cells have been extensively used for understanding the mechanisms by which some human enterovirulent bacteria induce intestinal disorders. Human colon carcinoma cell lines which are able to express in culture the functional and structural characteristics of mature enterocytes and goblet cells have been established, mimicking structurally and functionally an intestinal epithelial barrier. Moreover, Caco-2-derived M-like cells have been established, mimicking the bacterial capture property of M cells of Peyer's patches. This review intends to analyze the cellular and molecular mechanisms of pathogenesis of human enterovirulent bacteria observed in infected cultured human colon carcinoma enterocyte-like HT-29 subpopulations, enterocyte-like Caco-2 and clone cells, the colonic T84 cell line, HT-29 mucus-secreting cell subpopulations, and Caco-2-derived M-like cells, including cell association, cell entry, intracellular lifestyle, structural lesions at the brush border, functional lesions in enterocytes and goblet cells, functional and structural lesions at the junctional domain, and host cellular defense responses.

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The bacterial effectors EspG and EspG2 induce a destructive calpain activity that is kept in check by the co-delivered Tir effector

Cited by 28 publications

References 55 publications

The EspF Effector, a Bacterial Pathogen's Swiss Army Knife

The EspF Effector, a Bacterial Pathogen's Swiss Army Knife

Screening for Host Proteins Interacting with Escherichia Coli O157:H7 EspF using Bimolecular Fluorescence Complementation

Pathogenesis of Human Enterovirulent Bacteria: Lessons from Cultured, Fully Differentiated Human Colon Cancer Cell Lines

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