Cholera toxin: A paradigm for multi-functional engagement of cellular mechanisms (Review)

Abstract

Cholera toxin (Ctx) from Vibrio cholerae and its closely related homologue, heat-labile enterotoxin (Etx) from Escherichia coli have become superb tools for illuminating pathways of cellular trafficking and immune cell function. These bacterial protein toxins should be viewed as conglomerates of highly evolved, multi-functional elements equipped to engage the trafficking and signalling machineries of cells. Ctx and Etx are members of a larger family of A-B toxins of bacterial (and plant) origin that are comprised of structurally and functionally distinct enzymatically active A and receptor-binding B sub-units or domains. Intoxication of mammalian cells by Ctx and Etx involves B pentamer-mediated receptor binding and entry into a vesicular pathway, followed by translocation of the enzymatic A1 domain of the A sub-unit into the target cell cytosol, where covalent modification of intracellular targets leads to activation of adenylate cyclase and a sequence of events culminating in life-threatening diarrhoeal disease. Importantly, Ctx and Etx also have the capacity to induce a wide spectrum of remarkable immunological processes. With respect to the latter, it has been found that these toxins activate signalling pathways that modulate the immune system. This review explores the complexities of the cellular interactions that are engaged by these bacterial protein toxins, and highlights some of the new insights to have recently emerged.

An outer membrane channel protein of Mycobacterium tuberculosis with exotoxin activity

“…5C) is also consistent with the finding that ESX-1-mediated phagosomal rupture is followed by host cell necrosis within 48 h after infection (54). The ability of M. tuberculosis to enter and survive in macrophages and dendritic cells (6), and to escape from the phagosome, alleviates CpnT from the necessity of carrying an additional receptor-binding domain, as found in A-B-type toxins (57), to gain access to the cytosol of target cells.…”

Bacterial protein toxins and lipids: role in toxin targeting and activity

“…The whole toxin bound to GM1 receptors is then internalized into endocytic vesicles (Holmes et al, 1995). GM1 directs the toxin into lipid rafts from where it enters the Golgi via early and late endosomes (de Haan and Hirst, 2004). Golgi targeting of GM1 through caveolae is mediated by Rab7 and Rab9 (Choudhury et al, 2002).…”

“…The KDEL sequence may rather function to efficiently retain the toxins in the ER, allowing the A1 chain to be transported into the cytosol (Johannes et al, 1997;Fujinaga et al, 2003). The A1 fragment is responsible for the enzymatic activities of the toxin, including NAD hydrolysis in ADP-ribose and nicotinamide, and transfer of ADPribose to Arg 187 of the α-subunit of stimulatory protein (G αs ), leading to stimulation of AC and elevated intracellular cAMP (de Haan and Hirst, 2004).…”

“…According to the cell types and different studies, CT seems to enter cells via multiple ways, including clathrin-dependent and -independent, caveolae/raft, dynamin-independent and clathrin-dependent pathways (de Haan and Hirst, 2004). However, transport of CT from the plasma membrane to Golgi is mainly mediated by endosomes containing caveolin-1 and is independent of clathrin-coated pits (Nichols, 2002).…”

Functional Diversity of Heat-labile Toxins (LT) Produced by Enterotoxigenic Escherichia coli

“…The toxin is activated following cleavage of a trypsin-sensitive loop and reduction of the disulfide bridge, leaving the free A1 domain. The A1 domain carries the catalytic site, which is delimited by the ADP-binding crevice that binds to NAD and subsequently transfers the ADP-ribose moiety to the target protein (6). Several site-specific mutants contributed to the understanding of LT structural/functional relationships, such as LTK63, in which the serine at position 63 of the A1 domain active site was replaced with lysine (7,8).…”