Cytolethal Distending Toxin: A Unique Variation on the AB Toxin Paradigm

Table 1

The superfamily of AB toxins.

(a)

Class/Group	AB
Phylogeny	Eukarya (eukaryotes)					Bacteria (prokaryotes)
	plant					Gram-negative		Gram-positive
Common name	ricin	abrin subfamily			viscumin	diphtheria toxin (Dtx)	exotoxin A	botulinum toxin (Btx)	tetanus toxin (Ttx)
		abrin	modessin	volkensin
Source	Ricinus communis (caster bean)	Roary pea/Jequirity pea	Modecca digitata	Adenia volkensii Harms	Viscum album L (mistletoe)	Corynebacterium diphtheriae	Pseudomonas aeruginosa	Clostridium botulinum	Clostridium tetani
Toxic chain or subunit	N-glycoside hydrolase [type II ribosome inhibiting protein (RIP)]					NAD^+-diphthamide ADP-ribosyltransferase		protease
Cellular target	28S rRNA					elongation factor-2 (EF2)		cleavage of SNARE^c protein SNAP-25	cleavage of SNARE protein synaptobrevin II
Toxic activity	inhibits protein synthesis by hydrolysis of the N-glycosidic bond of an adenine residue in the sarcin-ricin loop of the 28S rRNA					inhibits protein synthesis by ribosylation of EF2		neurotoxicity due to prevention of release of the neurotransmitter acetylcholine	neurotoxicity due to prevention of release of the neurotransmitters glycine and γ-aminobutyric acid
Cell receptor	ganglioside GM3/glycoprotein/glycolipid					heparin-binding EGF-like (HB-EGF) receptor	lipoprotein receptor-related proteins LRP 1 and LRP 1B	GT1b

(b)

Class/Group	AB2	AB5						AB7	A2B7		?
Phylogeny	Bacteria (prokaryotes)
	Gram-negative							Gram-positive
Common name	cytolethal distending toxin (Cdt); subfamily	cholera toxin (Ctx)	Shiga toxin; (Stx)	pertussis toxin (Ptx)	subtilase cytotoxin	heat labile enterotoxin (LT-I and LT-II)	enterotoxin	iota	anthrax toxin (Atx)		exfoliatin B
									lethal factor (LF)	edema factor (EF)
Source	multiple genera^a	Vibrio cholerae	Shigella dysenteriae	Bordetella pertussis	Shiga toxigenic E. coli (STEC)	Escherichia coli	Campylobacter jejuni	Clostridium perfringens; Clostridium botulinum; Clostridium difficile	Bacillus anthracis		Staphylocococcus aureus
Toxic chain or subunit	mammalian type I; DNase/phosphatidylinositol-3,4,5-triphosphate 3-phosphatase (PTEN)	NAD^+-diphthamide; ADP-ribosyltransferase	N-glycoside; hydrolase [type II; ribosome inhibiting protein (RIP)]	NAD^+-diphthamide; ADP-ribosyltransferase	subtilase-like; serine protease	NAD^+-diphthamide; ADP-ribosyltransferase	antigenically; similar to Ctx	NAD^+-diphthamide; ADP-ribosyltransferase	Zn^2+-dependent endopeptidase F	calcium- and calmodulin (CaM)-dependent adenylyl cyclase	serine protease
Cellular target	nuclear DNA/phosphatidylinositol-3,4,5-triphosphate (PIP3)	guanosine nucleotide-binding proteins (G proteins)	28S rRNA	guanosine nucleotide-binding proteins (G proteins)	cleavage of BiP/GRP78 (Hsp70 family ER chaperone)	guanosine nucleotide-binding proteins (G proteins)		actin G	mitogen-activated protein kinases (MAPKK)	cAMP-induced changes of proteins	cadherin (desmoglein I)
Toxic activity	cell cycle arrest at G1 or G2/M; checkpoints/apoptosis^b	alters signal; transduction by ribosylation of G; proteins leading to increased; adenylate cyclase activity and ATP-mediated efflux of choride ions		alters signal; transduction by ribosylation of G; proteins leading to increased; adenylyl cyclase activity		alters signal; transduction by ribosylation of G; proteins leading to increased; adenylate cyclase activity and ATP-mediated efflux; of choride ions		ribosylation of actin G	removes N-terminal tail; of MAPKKs leading to; apoptosis	elevates the intracellular; cAMP concentration leading to; water efflux	detachment; of; epidermal; cells
Cell receptor	terminal β-D-galactopyranoside; glycoprotein or; glycolipid/ganglioside; GM3/TEM 181 (E. coli)	ganglioside GM1	glycolipid Gb3	ganglioside GD1a	N-glycolylneuraminic; acid terminal glycan	ganglioside GM1			ANTXR 1 (tumor endothelium marker-8 TEM8); ANTXR 2; (capillary morphogenesis protein-2 [CMG2])

See Table 2.
^bToxic activities are dependent on the species-specific Cdt and target cell.
^cSNARE, soluble N-ethylmaleimide-sensitive factor attachment.