title: Cholera toxin disrupts barrier function by inhibiting exocyst-mediated trafficking of host proteins to intestinal cell junctions.
abstract: Cholera toxin (CT), a virulence factor elaborated by Vibrio cholerae, is sufficient to induce the severe diarrhea characteristic of cholera. The enzymatic moiety of CT (CtxA) increases cAMP synthesis in intestinal epithelial cells, leading to chloride ion (Cl(-)) efflux through the CFTR Cl(-) channel. To preserve electroneutrality and osmotic balance, sodium ions and water also flow into the intestinal lumen via a paracellular route. We find that CtxA-driven cAMP increase also inhibits Rab11/exocyst-mediated trafficking of host proteins including E-cadherin and Notch signaling components to cell-cell junctions in Drosophila, human intestinal epithelial cells, and ligated mouse ileal loops, thereby disrupting barrier function. Additionally, CtxA induces junctional damage, weight loss, and dye leakage in the Drosophila gut, contributing to lethality from live V. cholerae infection, all of which can be rescued by Rab11 overexpression. These barrier-disrupting effects of CtxA may act in parallel with Cl(-) secretion to drive the pathophysiology of cholera.
authors.affiliation: Section of Cell and Developmental Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Annabel
authors.initials: A
authors.lastname: Guichard
authors.forename: Beatriz
authors.initials: B
authors.lastname: Cruz-Moreno
authors.forename: Beatriz Cruz
authors.initials: BC
authors.lastname: Cruz-Moreno
authors.forename: Berenice
authors.initials: B
authors.lastname: Aguilar
authors.forename: Nina M
authors.initials: NM
authors.lastname: van Sorge
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kuang
authors.forename: Adrianne A
authors.initials: AA
authors.lastname: Kurkciyan
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Wang
authors.forename: Saiyu
authors.initials: S
authors.lastname: Hang
authors.forename: Guillaume P
authors.initials: GP
authors.lastname: Pineton de Chambrun
authors.forename: Declan F
authors.initials: DF
authors.lastname: McCole
authors.forename: Paula
authors.initials: P
authors.lastname: Watnick
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Ethan
authors.initials: E
authors.lastname: Bier
mesh_terms: D000818:Animals; D002460:Cell Line; D002713:Chlorine / Q000378:metabolism; D002772:Cholera Toxin / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D055354:Exosomes / Q000187:drug effects*; D019204:GTP-Binding Proteins / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D008954:Models, Biological; D012964:Sodium / Q000378:metabolism; D016019:Survival Analysis; D062725:Tight Junction Proteins / Q000037:antagonists & inhibitors*; D019108:Tight Junctions / Q000187:drug effects / Q000502:physiology*; D014734:Vibrio cholerae / Q000502:physiology*; D014867:Water / Q000378:metabolism
chemical_list: D062725:Tight Junction Proteins; D014867:Water; D002713:Chlorine; D002772:Cholera Toxin; D012964:Sodium; D000242:Cyclic AMP; D019204:GTP-Binding Proteins
references.citation: Mol Biol Cell. 2009 Apr;20(8):2337-50
references.pmid: 19244346
references.citation: Infect Immun. 2011 Jul;79(7):2510-8
references.pmid: 21518787
references.citation: Development. 2010 Aug;137(16):2773-83
references.pmid: 20630948
references.citation: FEMS Immunol Med Microbiol. 1995 Feb;10(3-4):199-205
references.pmid: 7773236
references.citation: Development. 2004 May;131(9):2113-24
references.pmid: 15073155
references.citation: Lancet. 2004 Jan 17;363(9404):223-33
references.pmid: 14738797
references.citation: PLoS One. 2010 Aug 23;5(8):e12331
references.pmid: 20808795
references.citation: Dev Cell. 2005 Sep;9(3):365-76
references.pmid: 16224820
references.citation: Science. 1994 Oct 7;266(5182):107-9
references.pmid: 7524148
references.citation: J Cell Physiol. 2005 Jan;202(1):178-90
references.pmid: 15389533
references.citation: Dev Cell. 2009 May;16(5):633-47
references.pmid: 19460341
references.citation: Dev Cell. 2005 Sep;9(3):351-63
references.pmid: 16137928
references.citation: Nat New Biol. 1972 Jan 5;235(53):9-13
references.pmid: 4502409
references.citation: Development. 2004 Jan;131(2):377-88
references.pmid: 14681190
references.citation: Proc Natl Acad Sci U S A. 1982 May;79(10):3162-6
references.pmid: 6285339
references.citation: J Cell Sci. 2010 Jun 1;123(Pt 11):1913-21
references.pmid: 20460438
references.citation: Gastroenterology. 2011 Feb;140(2):550-9
references.pmid: 21056041
references.citation: Pharmacol Toxicol. 2002 Mar;90(3):109-20
references.pmid: 12071331
references.citation: Nature. 1965 Aug 7;207(997):614-6
references.pmid: 5883637
references.citation: PLoS Pathog. 2005 Sep;1(1):e8
references.pmid: 16201020
references.citation: Nature. 2010 Oct 14;467(7317):854-8
references.pmid: 20944747
references.citation: Mol Membr Biol. 2004 Mar-Apr;21(2):77-92
references.pmid: 15204437
references.citation: J Pathol Bacteriol. 1953 Oct;66(2):559-62
references.pmid: 13118463
references.citation: J Immunol. 2010 May 1;184(9):4852-62
references.pmid: 20368273
references.citation: Gastroenterology. 1989 Nov;97(5):1186-92
references.pmid: 2551764
references.citation: Am J Physiol. 1996 Mar;270(3 Pt 1):G515-25
references.pmid: 8638719
references.citation: J Biol Chem. 1992 Jun 25;267(18):12742-52
references.pmid: 1377674
references.citation: Mol Biol Cell. 2011 Dec;22(24):4787-800
references.pmid: 22013078
references.citation: Infect Immun. 1984 Jan;43(1):54-8
references.pmid: 6197380
references.citation: Development. 1993 Jun;118(2):401-15
references.pmid: 8223268
references.citation: Traffic. 2012 Jul;13(7):898-907
references.pmid: 22420621
references.citation: Cell Host Microbe. 2011 Nov 17;10(5):464-74
references.pmid: 22100162
references.citation: J Clin Invest. 1994 Jan;93(1):347-54
references.pmid: 7506713
references.citation: J Membr Biol. 1987;100(2):123-36
references.pmid: 3430569
references.citation: Dis Model Mech. 2011 Jan;4(1):21-30
references.pmid: 21183483
references.citation: Am J Physiol Gastrointest Liver Physiol. 2011 Jan;300(1):G82-98
references.pmid: 21030607
references.citation: Development. 1998 Feb;125(4):589-97
references.pmid: 9435280
references.citation: Gastroenterology. 1995 Aug;109(2):422-30
references.pmid: 7615191
references.citation: Cell Metab. 2011 Nov 2;14(5):623-34
references.pmid: 22055505
references.citation: Cell. 1991 Sep 6;66(5):1027-36
references.pmid: 1716180