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The Cell Biology of Toxins and Effector Proteins from Vibrio cholerae

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A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: closed (30 June 2015) | Viewed by 32303

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Special Issue Editor

Dr. Ken Teter

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Guest Editor

Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA
Interests: AB toxins; Cholera toxin; toxin translocation; endoplasmic reticulum-associated degradation; secretory traffic; chaperones; cell biology; cellular microbiology; host-pathogen interactions; structure-function analysis

Special Issue Information

Dear Colleagues,

Infection with Vibrio cholerae can lead to the life-threatening diarrheal disease of cholera. O1 and O139 serogroups of V. cholerae produce the cholera toxin (CT) which is primarily responsible for eliciting the characteristic rice-water stools of cholera. However, these strains produce additional toxins and effector proteins that contribute to the disease state. Non-O1/O139 strains of V. cholerae also produce toxins and effector proteins that play a role in pathogenesis. Elucidation of the cellular events involving these collective virulence factors will contribute to a holistic understanding of V. cholerae infections and could possibly lead to the development of novel therapeutic strategies, which will require appropriate animal models of infection. This special issue of Toxins will focus on the cell biology of V. cholerae toxins and effector proteins, therapeutic approaches that target those virulence factors, and animal models that can be used to test new therapeutic strategies.

Dr. Ken Teter
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

cholera toxin
effector proteins
non-O1/O139 Vibrio cholerae
host-toxin interactions
structure/function analysis
therapeutics
animal models

Published Papers (5 papers)

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Research

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1674 KiB

Open AccessArticle

Using S. cerevisiae as a Model System to Investigate V. cholerae VopX-Host Cell Protein Interactions and Phenotypes

by Christopher H. Seward, Alexander Manzella, Ashfaqul Alam, J. Scott Butler and Michelle Dziejman

Toxins 2015, 7(10), 4099-4110; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104099 - 14 Oct 2015

Cited by 6 | Viewed by 5631

Abstract

Most pathogenic, non-O1/non-O139 serogroup Vibrio cholerae strains cause diarrheal disease in the absence of cholera toxin. Instead, many use Type 3 Secretion System (T3SS) mediated mechanisms to disrupt host cell homeostasis. We identified a T3SS effector protein, VopX, which is translocated into mammalian cells during in vitro co-culture. In a S. cerevisiae model system, we found that expression of VopX resulted in a severe growth defect that was partially suppressed by a deletion of RLM1, encoding the terminal transcriptional regulator of the Cell Wall Integrity MAP kinase (CWI) regulated pathway. Growth of yeast cells in the presence of sorbitol also suppressed the defect, supporting a role for VopX in destabilizing the cell wall. Expression of VopX activated expression of β-galactosidase from an RLM1-reponsive element reporter fusion, but failed to do so in cells lacking MAP kinases upstream of Rlm1. The results suggest that VopX inhibits cell growth by stimulating the CWI pathway through Rlm1. Rlm1 is an ortholog of mammalian MEF2 transcription factors that are proposed to regulate cell differentiation, proliferation, and apoptosis. The collective findings suggest that VopX contributes to disease by activating MAP kinase cascades that elicit changes in cellular transcriptional programs. Full article

(This article belongs to the Special Issue The Cell Biology of Toxins and Effector Proteins from Vibrio cholerae)

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903 KiB

Open AccessArticle

Signaling beyond Punching Holes: Modulation of Cellular Responses by Vibrio cholerae Cytolysin

by Barkha Khilwani and Kausik Chattopadhyay

Toxins 2015, 7(8), 3344-3358; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7083344 - 21 Aug 2015

Cited by 22 | Viewed by 7401

Abstract

Pore-forming toxins (PFTs) are a distinct class of membrane-damaging cytolytic proteins that contribute significantly towards the virulence processes employed by various pathogenic bacteria. Vibrio cholerae cytolysin (VCC) is a prominent member of the beta-barrel PFT (beta-PFT) family. It is secreted by most of the pathogenic strains of the intestinal pathogen V. cholerae. Owing to its potent membrane-damaging cell-killing activity, VCC is believed to play critical roles in V. cholerae pathogenesis, particularly in those strains that lack the cholera toxin. Large numbers of studies have explored the mechanistic basis of the cell-killing activity of VCC. Consistent with the beta-PFT mode of action, VCC has been shown to act on the target cells by forming transmembrane oligomeric beta-barrel pores, thereby leading to permeabilization of the target cell membranes. Apart from the pore-formation-induced direct cell-killing action, VCC exhibits the potential to initiate a plethora of signal transduction pathways that may lead to apoptosis, or may act to enhance the cell survival/activation responses, depending on the type of target cells. In this review, we will present a concise view of our current understanding regarding the multiple aspects of these cellular responses, and their underlying signaling mechanisms, evoked by VCC. Full article

(This article belongs to the Special Issue The Cell Biology of Toxins and Effector Proteins from Vibrio cholerae)

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522 KiB

Open AccessArticle

A Conformational Shift in the Dissociated Cholera Toxin A1 Subunit Prevents Reassembly of the Cholera Holotoxin

by Michael Taylor, David Curtis and Ken Teter

Toxins 2015, 7(7), 2674-2684; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7072674 - 20 Jul 2015

Cited by 3 | Viewed by 5236

Abstract

Cholera toxin (CT) consists of a catalytic A1 subunit, an A2 linker, and a homopentameric cell-binding B subunit. The intact holotoxin moves by vesicle carriers from the cell surface to the endoplasmic reticulum (ER) where CTA1 is released from the rest of the toxin. The dissociated CTA1 subunit then shifts to an unfolded conformation, which triggers its export to the cytosol by a process involving the quality control system of ER-associated degradation (ERAD). We hypothesized that the unfolding of dissociated CTA1 would prevent its non-productive reassociation with CTA2/CTB₅. To test this prediction, we monitored the real-time reassociation of CTA1 with CTA2/CTB₅ by surface plasmon resonance. Folded but not disordered CTA1 could interact with CTA2/CTB₅ to form a stable, functional holotoxin. Our data, thus, identified another role for the intrinsic instability of the isolated CTA1 polypeptide in host-toxin interactions: in addition to activating the ERAD translocation mechanism, the spontaneous unfolding of free CTA1 at 37 °C prevents the non-productive reassembly of a CT holotoxin in the ER. Full article

(This article belongs to the Special Issue The Cell Biology of Toxins and Effector Proteins from Vibrio cholerae)

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2099 KiB

Open AccessArticle

A Mutational Analysis of Residues in Cholera Toxin A1 Necessary for Interaction with Its Substrate, the Stimulatory G Protein Gsα

by Michael G. Jobling, Lisa F. Gotow, Zhijie Yang and Randall K. Holmes

Toxins 2015, 7(3), 919-935; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7030919 - 18 Mar 2015

Cited by 11 | Viewed by 6441

Abstract

Pathogenesis of cholera diarrhea requires cholera toxin (CT)-mediated adenosine diphosphate (ADP)-ribosylation of stimulatory G protein (Gsα) in enterocytes. CT is an AB5 toxin with an inactive CTA1 domain linked via CTA2 to a pentameric receptor-binding B subunit. Allosterically activated CTA1 fragment in complex with NAD⁺ and GTP-bound ADP-ribosylation factor 6 (ARF6-GTP) differs conformationally from the CTA1 domain in holotoxin. A surface-exposed knob and a short α-helix (formed, respectively, by rearranging “active-site” and “activation” loops in inactive CTA1) and an ADP ribosylating turn-turn (ARTT) motif, all located near the CTA1 catalytic site, were evaluated for possible roles in recognizing Gsα. CT variants with one, two or three alanine substitutions at surface-exposed residues within these CTA1 motifs were tested for assembly into holotoxin and ADP-ribosylating activity against Gsα and diethylamino-(benzylidineamino)-guanidine (DEABAG), a small substrate predicted to fit into the CTA1 active site). Variants with single alanine substitutions at H55, R67, L71, S78, or D109 had nearly wild-type activity with DEABAG but significantly decreased activity with Gsα, suggesting that the corresponding residues in native CTA1 participate in recognizing Gsα. As several variants with multiple substitutions at these positions retained partial activity against Gsα, other residues in CTA1 likely also participate in recognizing Gsα. Full article

(This article belongs to the Special Issue The Cell Biology of Toxins and Effector Proteins from Vibrio cholerae)

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Review

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Open AccessReview

The Father, Son and Cholix Toxin: The Third Member of the DT Group Mono-ADP-Ribosyltransferase Toxin Family

by Miguel R. Lugo and A. Rod Merrill

Toxins 2015, 7(8), 2757-2772; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7082757 - 24 Jul 2015

Cited by 12 | Viewed by 6725

Abstract

The cholix toxin gene (chxA) was first identified in V. cholerae strains in 2007, and the protein was identified by bioinformatics analysis in 2008. It was identified as the third member of the diphtheria toxin group of mono-ADP-ribosyltransferase toxins along with P. aeruginosa exotoxin A and C. diphtheriae diphtheria toxin. Our group determined the structure of the full-length, three-domain cholix toxin at 2.1 Å and its C-terminal catalytic domain (cholix_c) at 1.25 Å resolution. We showed that cholix toxin is specific for elongation factor 2 (diphthamide residue), similar to exotoxin A and diphtheria toxin. Cholix toxin possesses molecular features required for infection of eukaryotes by receptor-mediated endocytosis, translocation to the host cytoplasm and inhibition of protein synthesis. More recently, we also solved the structure of full-length cholix toxin in complex with NAD⁺ and proposed a new kinetic model for cholix enzyme activity. In addition, we have taken a computational approach that revealed some important properties of the NAD⁺-binding pocket at the residue level, including the role of crystallographic water molecules in the NAD⁺ substrate interaction. We developed a pharmacophore model of cholix toxin, which revealed a cationic feature in the side chain of cholix toxin active-site inhibitors that may determine the active pose. Notably, several recent reports have been published on the role of cholix toxin as a major virulence factor in V. cholerae (non-O1/O139 strains). Additionally, FitzGerald and coworkers prepared an immunotoxin constructed from domains II and III as a cancer treatment strategy to complement successful immunotoxins derived from P. aeruginosa exotoxin A. Full article

(This article belongs to the Special Issue The Cell Biology of Toxins and Effector Proteins from Vibrio cholerae)

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