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...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2013-07-01
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| Series: | mBio |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00152-13 |
| _version_ | 1818740179288981504 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-18T01:36:37Z |
| format | Article |
| id | doaj.art-8c9ef27b55454017a72408007903b97f |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-18T01:36:37Z |
| publishDate | 2013-07-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-8c9ef27b55454017a72408007903b97f2022-12-21T21:25:26ZengAmerican Society for MicrobiologymBio2150-75112013-07-014310.1128/mBio.00152-13An <named-content content-type="genus-species">Escherichia coli</named-content> Effector Protein Promotes Host Mutation via Depletion of DNA Mismatch Repair ProteinsOliver David Kenneth Maddocks0Karen Mary Scanlon1Michael S. Donnenberg2Division of Infectious Diseases, Department of Medicine, University of Maryland, School of Medicine, Baltimore, Maryland, USADivision of Infectious Diseases, Department of Medicine, University of Maryland, School of Medicine, Baltimore, Maryland, USADivision of Infectious Diseases, Department of Medicine, University of Maryland, School of Medicine, Baltimore, Maryland, USAABSTRACT 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.https://journals.asm.org/doi/10.1128/mBio.00152-13 |
| spellingShingle | 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 mBio |
| 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_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_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_sort | named content content type genus species escherichia coli named content effector protein promotes host mutation via depletion of dna mismatch repair proteins |
| url | https://journals.asm.org/doi/10.1128/mBio.00152-13 |
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