skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Bile salt receptor complex activates a pathogenic type III secretion system

Abstract

Bile is an important component of the human gastrointestinal tract with an essential role in food absorption and antimicrobial activities. Enteric bacterial pathogens have developed strategies to sense bile as an environmental cue to regulate virulence genes during infection. We discovered that Vibrio parahaemolyticus VtrC, along with VtrA and VtrB, are required for activating the virulence type III secretion system 2 in response to bile salts. The VtrA/VtrC complex activates VtrB in the presence of bile salts. The crystal structure of the periplasmic domains of the VtrA/VtrC heterodimer reveals a β-barrel with a hydrophobic inner chamber. A co-crystal structure of VtrA/VtrC with bile salt, along with biophysical and mutational analysis, demonstrates that the hydrophobic chamber binds bile salts and activates the virulence network. As part of a family of conserved signaling receptors, VtrA/VtrC provides structural and functional insights into the evolutionarily conserved mechanism used by bacteria to sense their environment.

Authors:
; ; ; ; ORCiD logo; ; ORCiD logo
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1260282
Grant/Contract Number:
AC02-06CH11357
Resource Type:
Journal Article: Published Article
Journal Name:
eLife
Additional Journal Information:
Journal Volume: 5; Related Information: CHORUS Timestamp: 2017-06-24 13:48:16; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Country of Publication:
United States
Language:
English

Citation Formats

Li, Peng, Rivera-Cancel, Giomar, Kinch, Lisa N., Salomon, Dor, Tomchick, Diana R., Grishin, Nick V., and Orth, Kim. Bile salt receptor complex activates a pathogenic type III secretion system. United States: N. p., 2016. Web. doi:10.7554/eLife.15718.
Li, Peng, Rivera-Cancel, Giomar, Kinch, Lisa N., Salomon, Dor, Tomchick, Diana R., Grishin, Nick V., & Orth, Kim. Bile salt receptor complex activates a pathogenic type III secretion system. United States. doi:10.7554/eLife.15718.
Li, Peng, Rivera-Cancel, Giomar, Kinch, Lisa N., Salomon, Dor, Tomchick, Diana R., Grishin, Nick V., and Orth, Kim. 2016. "Bile salt receptor complex activates a pathogenic type III secretion system". United States. doi:10.7554/eLife.15718.
@article{osti_1260282,
title = {Bile salt receptor complex activates a pathogenic type III secretion system},
author = {Li, Peng and Rivera-Cancel, Giomar and Kinch, Lisa N. and Salomon, Dor and Tomchick, Diana R. and Grishin, Nick V. and Orth, Kim},
abstractNote = {Bile is an important component of the human gastrointestinal tract with an essential role in food absorption and antimicrobial activities. Enteric bacterial pathogens have developed strategies to sense bile as an environmental cue to regulate virulence genes during infection. We discovered that Vibrio parahaemolyticus VtrC, along with VtrA and VtrB, are required for activating the virulence type III secretion system 2 in response to bile salts. The VtrA/VtrC complex activates VtrB in the presence of bile salts. The crystal structure of the periplasmic domains of the VtrA/VtrC heterodimer reveals a β-barrel with a hydrophobic inner chamber. A co-crystal structure of VtrA/VtrC with bile salt, along with biophysical and mutational analysis, demonstrates that the hydrophobic chamber binds bile salts and activates the virulence network. As part of a family of conserved signaling receptors, VtrA/VtrC provides structural and functional insights into the evolutionarily conserved mechanism used by bacteria to sense their environment.},
doi = {10.7554/eLife.15718},
journal = {eLife},
number = ,
volume = 5,
place = {United States},
year = 2016,
month = 7
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.7554/eLife.15718

Save / Share:
  • Bile is an important component of the human gastrointestinal tract with an essential role in food absorption and antimicrobial activities. Enteric bacterial pathogens have developed strategies to sense bile as an environmental cue to regulate virulence genes during infection. We discovered that Vibrio parahaemolyticus VtrC, along with VtrA and VtrB, are required for activating the virulence type III secretion system 2 in response to bile salts. The VtrA/VtrC complex activates VtrB in the presence of bile salts. The crystal structure of the periplasmic domains of the VtrA/VtrC heterodimer reveals a β-barrel with a hydrophobic inner chamber. A co-crystal structure ofmore » VtrA/VtrC with bile salt, along with biophysical and mutational analysis, demonstrates that the hydrophobic chamber binds bile salts and activates the virulence network. As part of a family of conserved signaling receptors, VtrA/VtrC provides structural and functional insights into the evolutionarily conserved mechanism used by bacteria to sense their environment.« less
  • Bile is an important component of the human gastrointestinal tract with an essential role in food absorption and antimicrobial activities. Enteric bacterial pathogens have developed strategies to sense bile as an environmental cue to regulate virulence genes during infection. We discovered thatVibrio parahaemolyticusVtrC, along with VtrA and VtrB, are required for activating the virulence type III secretion system 2 in response to bile salts. The VtrA/VtrC complex activates VtrB in the presence of bile salts. The crystal structure of the periplasmic domains of the VtrA/VtrC heterodimer reveals a β-barrel with a hydrophobic inner chamber. A co-crystal structure of VtrA/VtrC withmore » bile salt, along with biophysical and mutational analysis, demonstrates that the hydrophobic chamber binds bile salts and activates the virulence network. As part of a family of conserved signaling receptors, VtrA/VtrC provides structural and functional insights into the evolutionarily conserved mechanism used by bacteria to sense their environment.« less
  • The persistent environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an ovarian toxicant. These studies were designed to characterize the actions of TCDD on steroidogenesis and growth of intact mouse antral follicles in vitro. Specifically, these studies tested the hypothesis that TCDD exposure leads to decreased sex hormone production/secretion by antral follicles as well as decreased growth of antral follicles in vitro. Since TCDD acts through binding to the aryl hydrocarbon receptor (AHR), and the AHR has been identified as an important factor in ovarian function, we also conducted experiments to confirm the presence and activation of the AHR in our tissue culturemore » system. To do so, we exposed mouse antral follicles for 96 h to a series of TCDD doses previously shown to have effects on ovarian tissues and cells in culture, which also encompass environmentally relevant and pharmacological exposures (0.1–100 nM), to determine a dose response for TCDD in our culture system for growth, hormone production, and expression of the Ahr and Cyp1b1. The results indicate that TCDD decreases progesterone, androstenedione, testosterone, and estradiol levels in a non-monotonic dose response manner without altering growth of antral follicles. The addition of pregnenolone substrate (10 μM) restores hormone levels to control levels. Additionally, Cyp1b1 levels were increased by 3–4 fold regardless of the dose of TCDD exposure, evidence of AHR activation. Overall, these data indicate that TCDD may act prior to pregnenolone formation and through AHR transcriptional control of Cyp1b1, leading to decreased hormone levels without affecting growth of antral follicles. -- Highlights: ►TCDD disrupts sex steroid hormone levels, but not growth of antral follicles. ►Pregnenolone co-treatment by-passes TCDD-induced steroid hormone disruption. ►TCDD affects steroid hormone levels through an AHR pathway in antral follicles.« less
  • Bile acids, which have been implicated in gastrointestinal-tract cell carcinogenesis, share properties with tumor promoters in that both affect signal transduction pathways responsible for cell proliferation and apoptosis. In the present study, we demonstrate that EGFR-ERK1/2 is activated following treatment of AGS human gastric carcinoma cells with bile acids. EGFR phosphoactivation is ligand-dependent, since treatment of cells with HB-EGF antisera or CM197 (a selective inhibitor of HB-EGF) markedly inhibits deoxycholate (DC)-promoted activation. Membrane-type bile acid receptor (M-BAR)/TGR5 is a recently identified G-protein-coupled receptor (GPCR). In AGS cells, siRNAs that target M-BAR suppress DC-induced phosphorylation of EGFR. Furthermore, introduction of siRNAsmore » targeting ADAM17 transcripts resulted in suppression of DC-induced activation of EGFR and ERK1/2. These results suggest that in AGS cells, DC transactivates EGFR through M-BAR- and ADAM/HB-EGF-dependent mechanisms.« less