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

Abstract

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.

Nano-Sized Hydroxyapatite Induces Apoptosis and Osteogenic Differentiation of Vascular Smooth Muscle Cells via JNK/c-JUN Pathway

“…Mitogen-activated protein kinases (MAPKs), represented by p38, JNK, and ERK1/2, are a common signaling pathway cascades in responding to extracellular stimulation. Since previous studies have shown that JNK phosphorylation is related with calcification in SMC, 16 , 17 we examined if nHAp activated JNK signaling pathway in SMCs. Significantly more phosphorylated JNK was detected after VSMCs were treated with nHAp for 15 min ( Figure 5A ).…”

“…Other reports also show that nHAp can activate other MAPK members, like p38 and ERK1/2 pathways. 16 , 17 , 53 Whether they are also involved in the process of calcification caused by nHAp remains to be proved.…”

Gut Microbiota and Diarrhea: An Updated Review

“…The cholera toxins, adnexa cholera toxin and closed band toxin produced by V. cholerae cause activation of anion secretion, inhibit absorption of electroneutral NaCl, destroy intestinal barrier function, and cause severe diarrhea (Ramamurthy et al, 2020). The serotypes O1 and O139 of V. cholerae strains with two main virulence genomes: cholera toxin (CT) and pathogenic toxin colonies cause an acute watery diarrhea (Ogura et al, 2020). A recent study showed that some non-01/O139 V. cholerae (NOVC) strains also cause diarrhea (Vezzulli et al, 2020).…”

Brown spider venom toxins: what are the functions of astacins, serine proteases, hyaluronidases, allergens, TCTP, serpins and knottins?

“…This clinical condition is histologically characterized as an aseptic coagulative necrosis, which consists of a massive destruction of skin structures without direct involvement of infectious agents [ 13 - 15 ]. This picture has a very intriguing mechanism, since the venom does not directly activate the leukocytes involved in the tissue destruction, but instead causes an initial activation of the endothelium, which in turn indirectly activates the leukocytes [ 16 , 17 ]. Signs like itching and skin rash in the vicinity of the bite site are also reported, which suggest an allergenic component in the venom [ 3 , 6 , 8 , 10 , 18 , 19 ].…”

“…They are related to the uncontrolled activation of inflammatory response that appears after envenoming, which results in the skin injury, in addition to triggering the systemic deleterious processes previously mentioned. Herein, phospholipases D will not be explored, since updated data on them were extensively reviewed in recent publications [ 6 , 17 , 28 , 29 ].…”