title: An Escherichia coli 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 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.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Maryland, School of Medicine, Baltimore, Maryland, USA.
authors.forename: Oliver David Kenneth
authors.initials: OD
authors.lastname: Maddocks
authors.forename: Karen Mary
authors.initials: KM
authors.lastname: Scanlon
authors.forename: Michael S
authors.initials: MS
authors.lastname: Donnenberg
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000378:metabolism*; D054308:Enteropathogenic Escherichia coli / Q000235:genetics* / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D059645:Mutation Rate; D021381:Protein Transport; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D029968:Escherichia coli Proteins; C489109:EspFU protein, E coli; D047908:Intracellular Signaling Peptides and Proteins; D037521:Virulence Factors; D045643:DNA Repair Enzymes