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. 2013 Dec 10;3(4):997-1029.
doi: 10.3390/biom3040997.

Toxin instability and its role in toxin translocation from the endoplasmic reticulum to the cytosol

Ken Teter  1
Affiliations

Toxin instability and its role in toxin translocation from the endoplasmic reticulum to the cytosol

Ken Teter. Biomolecules. .

Abstract

AB toxins enter a host cell by receptor-mediated endocytosis. The catalytic A chain then crosses the endosome or endoplasmic reticulum (ER) membrane to reach its cytosolic target. Dissociation of the A chain from the cell-binding B chain occurs before or during translocation to the cytosol, and only the A chain enters the cytosol. In some cases, AB subunit dissociation is facilitated by the unique physiology and function of the ER. The A chains of these ER-translocating toxins are stable within the architecture of the AB holotoxin, but toxin disassembly results in spontaneous or assisted unfolding of the isolated A chain. This unfolding event places the A chain in a translocation-competent conformation that promotes its export to the cytosol through the quality control mechanism of ER-associated degradation. A lack of lysine residues for ubiquitin conjugation protects the exported A chain from degradation by the ubiquitin-proteasome system, and an interaction with host factors allows the cytosolic toxin to regain a folded, active state. The intrinsic instability of the toxin A chain thus influences multiple steps of the intoxication process. This review will focus on the host-toxin interactions involved with A chain unfolding in the ER and A chain refolding in the cytosol.

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Figures

Figure 1
Figure 1
Intracellular toxin trafficking. The general trafficking and translocation itinerary for AB-type, endoplasmic reticulum (ER)-translocating toxins is shown. These toxins bind to distinct surface receptors and are internalized by a variety of endocytic mechanisms. The internalized toxin is recycled to the plasma membrane, directed to the lysosomes for degradation, or delivered to the trans-Golgi network (TGN) en route to the ER translocation site. Vesicle-mediated transport to the TGN can originate from the early or late endosomes, depending on which toxin is present. Likewise, multiple retrograde transport pathways can deliver the toxin from the TGN to the ER. The toxin may cycle between the Golgi and ER until the catalytic subunit dissociates from the rest of the toxin and shifts to an unfolded conformation which triggers its export to the cytosol in a process involving the quality control system of ER-associated degradation. Some of the free, ER-localized A chain escapes ER-associated degradation (ERAD) and is secreted back into the medium via Golgi and TGN intermediates. In most cell types, trafficking from the cell surface to the ER is very inefficient: the majority of internalized toxin is routed to the lysosomes, and only around 10% of surface-bound toxin reaches the ER [9,10,11,12,13,14,15,16]. Thus, ectopic expression of an ER-localized A chain via transfected cultured cells, transformed yeast, or microsomal transcription/translation systems is often used for toxin translocation studies.
Figure 2
Figure 2
Structural organization of AB-type, ER-translocating toxins. (a) Ribbon diagram of cholera toxin (Ctx; PDB 1S5F, [33]). The A1 subunit is in blue; the A2 linker is red; and the B homopentamer is grey. The CtxB pentamer recognizes GM1 gangliosides on the host cell surface, while CtxA1 is an ADP-ribosyltransferase that elevates intracellular cAMP levels by activating the stimulatory α subunit of the heterotrimeric G protein; (b) Ribbon diagram of ricin toxin (Rtx; PDB 2AAI, [34]). RtxA is in blue, and RtxB is in grey. RtxB binds to a wide range of glycoproteins and glycolipids with terminal galactose residues, while RtxA is an N-glycosidase that inhibits protein synthesis by removing a specific adenine residue from the 28S rRNA; (c) Ribbon diagram of pertussis toxin (Ptx; PDB 1PRT, [35]). The catalytic S1 subunit is in blue, and the five subunits of the B pentamer (S2, S3, two copies of S4, and S5) are grey. PtxB can bind to a variety of glycoconjugates, while PtxS1 is an ADP-ribosyltransferase that elevates intracellular cAMP levels by locking the inhibitory α subunit of the heterotrimeric G protein in an inactive state; (d) Ribbon diagram of Shiga toxin (Stx; PDB 1DM0, [36]). The A1 subunit is in blue; the A2 linker is in red; and the B homopentamer is grey. The StxB pentamer binds to globoside Gb3 on the host cell surface, while StxA1 is an N-glycosidase that inhibits protein synthesis by removing a specific adenine residue from the 28S rRNA. The Stx family includes Stx from Shigella dysenteriae (pictured) and the Shiga-like toxins (Stx1, Stx2, and Stx2 isoforms) from Escherichia coli; (e) Ribbon diagram of Pseudomonas aeruginosa exotoxin A (EtxA; PDB 1IKQ, [37]). The catalytic moiety (domain III) is in blue, and the B moiety (domains I and II) is in grey. The B moiety of EtxA binds to the α-macroglobulin receptor/low density lipoprotein receptor-related protein on the host plasma membrane, while the A moiety of EtxA is an ADP-ribosyltransferase that inhibits protein synthesis through the modification of elongation factor 2; (f) Ribbon diagram of cytolethal distending toxin (Cdtx; PDB 1SR4, [38]). The catalytic CdtxB subunit is in blue, while the cell-binding CdtxA and CdtxC subunits are in grey. The cell-binding heterodimer binds to cholesterol and glycoconjugates, while the CdtxB subunit is a type I DNase that induces cell cycle arrest by causing double-stranded DNA breaks.
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References

    1. Barth H. Exploring the role of host cell chaperones/PPIases during cellular up-take of bacterial ADP-ribosylating toxins as basis for novel pharmacological strategies to protect mammalian cells against these virulence factors. Naunyn. Schmiedebergs. Arch. Pharmacol. 2011;383:237–245. doi: 10.1007/s00210-010-0581-y. - DOI - PubMed
    1. Sandvig K., van Deurs B. Membrane traffic exploited by protein toxins. Annu. Rev. Cell Dev. Biol. 2002;18:1–24. doi: 10.1146/annurev.cellbio.18.011502.142107. - DOI - PubMed
    1. Ivarsson M.E., Leroux J.C., Castagner B. Targeting bacterial toxins. Angew. Chem. Int. Ed. Engl. 2012;51:4024–4045. doi: 10.1002/anie.201104384. - DOI - PubMed
    1. Wernick N.L.B., Chinnapen D.J.-F., Cho J.A., Lencer W.I. Cholera toxin: an intracellular journey into the cytosol by way of the endoplasmic reticulum. Toxins. 2010;2:310–325. doi: 10.3390/toxins2030310. - DOI - PMC - PubMed
    1. Lord J.M., Spooner R.A. Ricin trafficking in plant and mammalian cells. Toxins. 2011;3:787–801. doi: 10.3390/toxins3070787. - DOI - PMC - PubMed

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