Enteropathogenic Escherichia coli EspH-Mediated Rho GTPase Inhibition Results in Desmosomal Perturbations
Name:
1-s2.0-S2352345X18300675-main.pdf
Size:
6.202Mb
Format:
PDF
Description:
Final Published version
Author
Roxas, Jennifer LisingMonasky, Ross Calvin
Roxas, Bryan Angelo P.
Agellon, Al B.
Mansoor, Asad
Kaper, James B.
Vedantam, Gayatri
Viswanathan, V.K.
Affiliation
Univ Arizona, Sch Anim & Comparat Biomed SciUniv Arizona, BIO5 Inst Collaborat Res
Univ Arizona, Dept Immunobiol
Issue Date
2018
Metadata
Show full item recordPublisher
ELSEVIER INCCitation
Jennifer Lising Roxas, Ross Calvin Monasky, Bryan Angelo P. Roxas, Al B. Agellon, Asad Mansoor, James B. Kaper, Gayatri Vedantam, V.K. Viswanathan, Enteropathogenic Escherichia coli EspH-Mediated Rho GTPase Inhibition Results in Desmosomal Perturbations, Cellular and Molecular Gastroenterology and Hepatology, 6(2), 2018, pp 163-180, https://doi.org/10.1016/j.jcmgh.2018.04.007.Rights
© 2018 The Authors. Published by Elsevier Inc. on behalf of the AGA Institute. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
BACKGROUND & AIMS: The diarrheagenic pathogen, enteropathogenic Escherichia coli (EPEC), uses a type III secretion system to deliver effector molecules into intestinal epithelial cells (IECs). While exploring the basis for the lateral membrane separation of EPEC-infected IECs, we observed infection-induced loss of the desmosomal cadherin desmoglein-2 (DSG2). We sought to identify the molecule(s) involved in, and delineate the mechanisms and consequences of, EPEC-induced DSG2 loss. METHODS: DSG2 abundance and localization was monitored via immunoblotting and immunofluorescence, respectively. Junctional perturbations were visualized by electron microscopy, and cell-cell adhesion was assessed using dispase assays. EspH alanine-scan mutants as well as pharmacologic agents were used to evaluate impacts on desmosomal alterations. EPEC-mediated DSG2 loss, and its impact on bacterial colonization in vivo, was assessed using a murine model. RESULTS: The secreted virulence protein EspH mediates EPEC-induced DSG2 degradation, and contributes to desmosomal perturbation, loss of cell junction integrity, and barrier disruption in infected IECs. EspH sequesters Rho guanine nucleotide exchange factors and inhibits Rho guanosine triphosphatase signaling; EspH mutants impaired for Rho guanine nucleotide exchange factor interaction failed to inhibit RhoA or deplete DSG2. Cytotoxic necrotizing factor 1, which locks Rho guanosine triphosphatase in the active state, jasplakinolide, a molecule that promotes actin polymerization, and the lysosomal inhibitor bafilomycin A, respectively, rescued infected cells from EPEC-induced DSG2 loss. Wild-type EPEC, but not an espH-deficient strain, colonizes mouse intestines robustly, widens paracellular junctions, and induces DSG2 re-localization in vivo. CONCLUSIONS: Our studies define the mechanism and consequences of EPEC-induced desmosomal alterations in IECs. These perturbations contribute to the colonization and virulence of EPEC, and likely related pathogens. (Cell Mol Gastroenterol Hepatol 2018;6:163-180; https:/doi.org/10.1016/j.jcmgh.2018.04.007)Note
Open access journal.ISSN
2352345XPubMed ID
30003123Version
Final published versionSponsors
National Institutes of Health [NIAID1R01AI081742, 1S10OD011981-01]; United States Department of Agriculture Co-op Research and Extension Services (USDA CSREES) Hatch Program [ARZT-5704100-A02-140, ARZT-570410-A-02-139]; US Department of Veterans Affairs [1I01BX001183-01]Additional Links
https://linkinghub.elsevier.com/retrieve/pii/S2352345X18300675ae974a485f413a2113503eed53cd6c53
10.1016/j.jcmgh.2018.04.007
Scopus Count
Collections
Except where otherwise noted, this item's license is described as © 2018 The Authors. Published by Elsevier Inc. on behalf of the AGA Institute. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Related articles
- Epithelial maturity influences EPEC-induced desmosomal alterations.
- Authors: Roxas JL, Vedantam G, Viswanathan VK
- Issue date: 2019
- Enteropathogenic Escherichia coli regulates host-cell mitochondrial morphology.
- Authors: Roxas JL, Ramamurthy S, Cocchi K, Rutins I, Harishankar A, Agellon A, Wilbur JS, Sylejmani G, Vedantam G, Viswanathan VK
- Issue date: 2022 Jan-Dec
- The interplay between the Escherichia coli Rho guanine nucleotide exchange factor effectors and the mammalian RhoGEF inhibitor EspH.
- Authors: Wong AR, Clements A, Raymond B, Crepin VF, Frankel G
- Issue date: 2012
- The enteropathogenic E. coli effector EspH promotes actin pedestal formation and elongation via WASP-interacting protein (WIP).
- Authors: Wong AR, Raymond B, Collins JW, Crepin VF, Frankel G
- Issue date: 2012 Jul
- Enteropathogenic Escherichia coli (EPEC) Recruitment of PAR Polarity Protein Atypical PKCζ to Pedestals and Cell-Cell Contacts Precedes Disruption of Tight Junctions in Intestinal Epithelial Cells.
- Authors: Tapia R, Kralicek SE, Hecht GA
- Issue date: 2020 Jan 14