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Cell Death Signaling Pathway Induced by Cholix Toxin, a Cytotoxin and eEF2 ADP-Ribosyltransferase Produced by Vibrio cholerae

1
Advanced Health Care Science Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa 920-0942, Japan
2
Department of Molecular Infectiology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
3
Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1590, USA
*
Authors to whom correspondence should be addressed.
Toxins 2021, 13(1), 12; https://doi.org/10.3390/toxins13010012
Received: 27 October 2020 / Revised: 20 December 2020 / Accepted: 22 December 2020 / Published: 24 December 2020
(This article belongs to the Special Issue Structure and Function of Bacterial ADP-Ribosylation Toxins)
Pathogenic microorganisms produce various virulence factors, e.g., enzymes, cytotoxins, effectors, which trigger development of pathologies in infectious diseases. Cholera toxin (CT) produced by O1 and O139 serotypes of Vibrio cholerae (V. cholerae) is a major cytotoxin causing severe diarrhea. Cholix cytotoxin (Cholix) was identified as a novel eukaryotic elongation factor 2 (eEF2) adenosine-diphosphate (ADP)-ribosyltransferase produced mainly in non-O1/non-O139 V. cholerae. The function and role of Cholix in infectious disease caused by V. cholerae remain unknown. The crystal structure of Cholix is similar to Pseudomonas exotoxin A (PEA) which is composed of an N-terminal receptor-recognition domain and a C-terminal ADP-ribosyltransferase domain. The endocytosed Cholix catalyzes ADP-ribosylation of eEF2 in host cells and inhibits protein synthesis, resulting in cell death. In a mouse model, Cholix caused lethality with severe liver damage. In this review, we describe the mechanism underlying Cholix-induced cytotoxicity. Cholix-induced apoptosis was regulated by mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathways, which dramatically enhanced tumor necrosis factor-α (TNF-α) production in human liver, as well as the amount of epithelial-like HepG2 cancer cells. In contrast, Cholix induced apoptosis in hepatocytes through a mitochondrial-dependent pathway, which was not stimulated by TNF-α. These findings suggest that sensitivity to Cholix depends on the target cell. A substantial amount of information on PEA is provided in order to compare/contrast this well-characterized mono-ADP-ribosyltransferase (mART) with Cholix. View Full-Text
Keywords: bacterial cytotoxin; ADP-ribosyltransferase; mono-ADP-ribosylation; cell death; apoptosis; hepatocytes bacterial cytotoxin; ADP-ribosyltransferase; mono-ADP-ribosylation; cell death; apoptosis; hepatocytes
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MDPI and ACS Style

Ogura, K.; Yahiro, K.; Moss, J. Cell Death Signaling Pathway Induced by Cholix Toxin, a Cytotoxin and eEF2 ADP-Ribosyltransferase Produced by Vibrio cholerae. Toxins 2021, 13, 12. https://doi.org/10.3390/toxins13010012

AMA Style

Ogura K, Yahiro K, Moss J. Cell Death Signaling Pathway Induced by Cholix Toxin, a Cytotoxin and eEF2 ADP-Ribosyltransferase Produced by Vibrio cholerae. Toxins. 2021; 13(1):12. https://doi.org/10.3390/toxins13010012

Chicago/Turabian Style

Ogura, Kohei; Yahiro, Kinnosuke; Moss, Joel. 2021. "Cell Death Signaling Pathway Induced by Cholix Toxin, a Cytotoxin and eEF2 ADP-Ribosyltransferase Produced by Vibrio cholerae" Toxins 13, no. 1: 12. https://doi.org/10.3390/toxins13010012

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