An <named-content content-type="genus-species">Escherichia coli</named-content> Effector Protein Promotes Host Mutation via Depletion of DNA Mismatch Repair Proteins

ABSTRACT Enteropathogenic Escherichia coli (EPEC) is an attaching and effacing (A/E) human pathogen that causes diarrhea during acute infection, and it can also sustain asymptomatic colonization. A/E E. coli depletes host cell DNA mismatch repair (MMR) proteins in colonic cell lines and has been det...

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Autores principales:	Oliver David Kenneth Maddocks, Karen Mary Scanlon, Michael S. Donnenberg
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8c9ef27b55454017a72408007903b97f
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spelling	oai:doaj.org-article:8c9ef27b55454017a72408007903b97f2021-11-15T15:40:05ZAn <named-content content-type="genus-species">Escherichia coli</named-content> Effector Protein Promotes Host Mutation via Depletion of DNA Mismatch Repair Proteins10.1128/mBio.00152-132150-7511https://doaj.org/article/8c9ef27b55454017a72408007903b97f2013-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00152-13https://doaj.org/toc/2150-7511ABSTRACT Enteropathogenic Escherichia coli (EPEC) is an attaching and effacing (A/E) human pathogen that causes diarrhea during acute infection, and it can also sustain asymptomatic colonization. A/E E. coli depletes host cell DNA mismatch repair (MMR) proteins in colonic cell lines and has been detected in colorectal cancer (CRC) patients. However, until now, a direct link between infection and host mutagenesis has not been fully demonstrated. Here we show that the EPEC-secreted effector protein EspF is critical for complete EPEC-induced depletion of MMR proteins. The mechanism of EspF activity on MMR protein was posttranscriptional and dependent on EspF mitochondrial targeting. EPEC infection also induced EspF-independent elevation of host reactive oxygen species levels. Moreover, EPEC infection significantly increased spontaneous mutation frequency in host cells, and this effect was dependent on mitochondrially targeted EspF. Taken together, these results support the hypothesis that A/E E. coli can promote colorectal carcinogenesis in humans. IMPORTANCE There is mounting evidence linking the gut microbiota with the induction of colorectal tumorigenesis. We previously described the downregulation of host cell mismatch repair (MMR) protein levels upon enteropathogenic Escherichia coli (EPEC) infection and speculated that this depletion may lead to an ablated DNA repair system. In this work, we identify EspF, a translocated EPEC effector protein, as one of the factors required for this phenotype and show that this effector protein must be targeted to the mitochondria in order to exert its effect. Furthermore, we found that the impaired mismatch repair system resulting from EPEC infection led to the generation of spontaneous mutations within host DNA at a site of microsatellite instability, a trait typical of colorectal tumors. Thus, this work provides a novel means by which enteric bacteria may promote colorectal carcinogenesis.Oliver David Kenneth MaddocksKaren Mary ScanlonMichael S. DonnenbergAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 3 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Oliver David Kenneth Maddocks Karen Mary Scanlon Michael S. Donnenberg An <named-content content-type="genus-species">Escherichia coli</named-content> Effector Protein Promotes Host Mutation via Depletion of DNA Mismatch Repair Proteins
description	ABSTRACT Enteropathogenic Escherichia coli (EPEC) is an attaching and effacing (A/E) human pathogen that causes diarrhea during acute infection, and it can also sustain asymptomatic colonization. A/E E. coli depletes host cell DNA mismatch repair (MMR) proteins in colonic cell lines and has been detected in colorectal cancer (CRC) patients. However, until now, a direct link between infection and host mutagenesis has not been fully demonstrated. Here we show that the EPEC-secreted effector protein EspF is critical for complete EPEC-induced depletion of MMR proteins. The mechanism of EspF activity on MMR protein was posttranscriptional and dependent on EspF mitochondrial targeting. EPEC infection also induced EspF-independent elevation of host reactive oxygen species levels. Moreover, EPEC infection significantly increased spontaneous mutation frequency in host cells, and this effect was dependent on mitochondrially targeted EspF. Taken together, these results support the hypothesis that A/E E. coli can promote colorectal carcinogenesis in humans. IMPORTANCE There is mounting evidence linking the gut microbiota with the induction of colorectal tumorigenesis. We previously described the downregulation of host cell mismatch repair (MMR) protein levels upon enteropathogenic Escherichia coli (EPEC) infection and speculated that this depletion may lead to an ablated DNA repair system. In this work, we identify EspF, a translocated EPEC effector protein, as one of the factors required for this phenotype and show that this effector protein must be targeted to the mitochondria in order to exert its effect. Furthermore, we found that the impaired mismatch repair system resulting from EPEC infection led to the generation of spontaneous mutations within host DNA at a site of microsatellite instability, a trait typical of colorectal tumors. Thus, this work provides a novel means by which enteric bacteria may promote colorectal carcinogenesis.
format	article
author	Oliver David Kenneth Maddocks Karen Mary Scanlon Michael S. Donnenberg
author_facet	Oliver David Kenneth Maddocks Karen Mary Scanlon Michael S. Donnenberg
author_sort	Oliver David Kenneth Maddocks
title	An <named-content content-type="genus-species">Escherichia coli</named-content> Effector Protein Promotes Host Mutation via Depletion of DNA Mismatch Repair Proteins
title_short	An <named-content content-type="genus-species">Escherichia coli</named-content> Effector Protein Promotes Host Mutation via Depletion of DNA Mismatch Repair Proteins
title_full	An <named-content content-type="genus-species">Escherichia coli</named-content> Effector Protein Promotes Host Mutation via Depletion of DNA Mismatch Repair Proteins
title_fullStr	An <named-content content-type="genus-species">Escherichia coli</named-content> Effector Protein Promotes Host Mutation via Depletion of DNA Mismatch Repair Proteins
title_full_unstemmed	An <named-content content-type="genus-species">Escherichia coli</named-content> Effector Protein Promotes Host Mutation via Depletion of DNA Mismatch Repair Proteins
title_sort	<named-content content-type="genus-species">escherichia coli</named-content> effector protein promotes host mutation via depletion of dna mismatch repair proteins
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/8c9ef27b55454017a72408007903b97f
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An <named-content content-type="genus-species">Escherichia coli</named-content> Effector Protein Promotes Host Mutation via Depletion of DNA Mismatch Repair Proteins

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