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Review
. 2012 Apr 11:2:51.
doi: 10.3389/fcimb.2012.00051. eCollection 2012.

Insights on the trafficking and retro-translocation of glycosphingolipid-binding bacterial toxins

Jin A Cho  1 , Daniel J-F Chinnapen, Emil Aamar, Yvonne M te Welscher, Wayne I Lencer, Ramiro Massol
Affiliations
Review

Insights on the trafficking and retro-translocation of glycosphingolipid-binding bacterial toxins

Jin A Cho et al. Front Cell Infect Microbiol. .

Abstract

Some bacterial toxins and viruses have evolved the capacity to bind mammalian glycosphingolipids to gain access to the cell interior, where they can co-opt the endogenous mechanisms of cellular trafficking and protein translocation machinery to cause toxicity. Cholera toxin (CT) is one of the best-studied examples, and is the virulence factor responsible for massive secretory diarrhea seen in cholera. CT enters host cells by binding to monosialotetrahexosylganglioside (GM1 gangliosides) at the plasma membrane where it is transported retrograde through the trans-Golgi network (TGN) into the endoplasmic reticulum (ER). In the ER, a portion of CT, the CT-A1 polypeptide, is unfolded and then "retro-translocated" to the cytosol by hijacking components of the ER associated degradation pathway (ERAD) for misfolded proteins. CT-A1 rapidly refolds in the cytosol, thus avoiding degradation by the proteasome and inducing toxicity. Here, we highlight recent advances in our understanding of how the bacterial AB(5) toxins induce disease. We highlight the molecular mechanisms by which these toxins use glycosphingolipid to traffic within cells, with special attention to how the cell senses and sorts the lipid receptors. We also discuss several new studies that address the mechanisms of toxin unfolding in the ER and the mechanisms of CT A1-chain retro-translocation to the cytosol.

Keywords: ERAD; cholera toxin; membrane trafficking; retro-translocation.

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Figures

Figure 1
Figure 1
Retrograde trafficking and retro-translocation of AB5 toxins in host cells. (1) AB5 toxins such as CT and ST, bind to glycosphingolipids located on the outer leaflet of the plasma membrane. (2) In the case of CT, the binding to the ganglioside GM1 effectively clusters the lipid on the cell surface, where endocytosis can occur by clathrin-dependent, or–independent routes. This is known to involve flotillin proteins that can sense membrane microdomains. All internalization pathways converge into the early/sorting endosome compartment (EE/SE), where sorting occurs to the TGN (aided by SNARE proteins Syntaxin 5, Syntaxin 6, Syntaxin 16, and the retromer complex) (3a), to the recycling endosome (via Rab4, Rab5 and Rab11) (3b), or to late endosomes (not shown). (4) From the Golgi, CT is transported to the ER where the A-subunit is dissociated from the B-chain with the aid of PDI and Ero1p. (5) The A-chain is then unfolded by the ERdj3/HEDJ complex along with BiP, where it is translocated across the ER membrane into the cytosol with the aid of TorsinA, gp78/Hrd1 and Derlin-1. (6) Once in the cytosol, the A-chain rapidly refolds in an Hsp90-dependent manner where its catalytic activity stimulates adenylate cyclase (AC) resulting in an intracellular increase of cAMP (7).
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