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This article is part of the Research Topic Critical advances in the study of bacterial toxins


Front. Cell. Infect. Microbiol., 11 April 2012 | http://dx.doi.org/10.3389/fcimb.2012.00051

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

Jin A. Cho1,3, Daniel J.-F. Chinnapen1,3, Emil Aamar1,3, Yvonne M. te Welscher1,3, Wayne I. Lencer1,2,3* and Ramiro Massol1,2,3*
  • 1Division of Gastroenterology and Nutrition, Department of Medicine, Children's Hospital Boston, Boston, MA, USA
  • 2Harvard Digestive Diseases Center, Boston, MA, USA
  • 3Department of Pediatrics, Harvard Medical School, Boston, MA, USA

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 AB5 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: cholera toxin, membrane trafficking, retro-translocation, ERAD

Citation: Cho JA, Chinnapen D J-F, Aamar E, te Welscher YM, Lencer WI and Massol R (2012) Insights on the trafficking and retro-translocation of glycosphingolipid-binding bacterial toxins. Front. Cell. Inf. Microbio. 2:51. doi:10.3389/fcimb.2012.00051

Received: 24 January 2012; Accepted: 24 March 2012;
Published online: 11 April 2012.

Edited by:

Ken Bradley, University of California, Los Angeles, USA

Reviewed by:

Vincent J. Starai, The University of Georgia, USA
Vernon L. Tesh, Texas A&M University Health Science Center, USA

Copyright: © 2012 Cho, Chinnapen, Aamar, te Welscher, Lencer and Massol. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

*Correspondence: Ramiro Massol and Wayne I. Lencer, Division of Gastroenterology and Nutrition, Children's Hospital Boston, 300 Longwood Avenue, Enders Bldg. Rm. 609, Boston, MA 02115, USA. e-mail: ramiro.massol@childrens.harvard.edu; wayne.lencer@childrens.harvard.edu