title: Enterotoxigenic Escherichia coli prevents host NF-κB activation by targeting IκBα polyubiquitination.
abstract: The NF-κB pathway regulates innate immune responses to infection. NF-κB is activated after pathogen-associated molecular patterns are detected, leading to the induction of proinflammatory host responses. As a countermeasure, bacterial pathogens have evolved mechanisms to subvert NF-κB signaling. Enterotoxigenic Escherichia coli (ETEC) causes diarrheal disease and significant morbidity and mortality for humans in developing nations. The extent to which this important pathogen subverts innate immune responses by directly targeting the NF-κB pathway is an understudied topic. Here we report that ETEC secretes a heat-stable, proteinaceous factor that blocks NF-κB signaling normally induced by tumor necrosis factor (TNF), interleukin-1β, and flagellin. Pretreating intestinal epithelial cells with ETEC supernatant significantly blocked the degradation of the NF-κB inhibitor IκBα without affecting IκBα phosphorylation. Data from immunoprecipitation experiments suggest that the ETEC factor functions by preventing IκBα polyubiquitination. Inhibiting clathrin function blocked the activity of the secreted ETEC factor, suggesting that this yet-uncharacterized activity may utilize clathrin-dependent endocytosis to enter host cells. These data suggest that ETEC evades the host innate immune response by directly modulating NF-κB signaling.
authors.affiliation: Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Wang
authors.forename: Philip R
authors.initials: PR
authors.lastname: Hardwidge
mesh_terms: D000818:Animals; D002460:Cell Line; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis; D054307:Enterotoxigenic Escherichia coli / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007113:Immunity, Innate; D007422:Intestines / Q000166:cytology / Q000382:microbiology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination / Q000187:drug effects*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D002966:Clathrin; D029968:Escherichia coli Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D037521:Virulence Factors; D000072000:NF-KappaB Inhibitor alpha