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A more recent version of this article appeared on December 1, 2003
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Submitted on June 2, 2003
Revised on July 9, 2003
Accepted on August 7, 2003
1 GI Cell Biology, Children's Hospital and Harvard
Medical School, Department of Bacteriology, Okayama
University Graduate School of Medicine and Dentistry, 2-5-1
Shikata-cho, Okayama, 700-8558, and PRESTO, Japan Science and
Technology Corporation, Japan
2 GI Cell Biology, Children's Hospital and Harvard Medical School
3 GI Cell Biology, Children's Hospital and Harvard
Medical School
4 Cell Biology, Harvard Medical School, Boston 02115
5 Department of Microbiology, University of Colorado Health Sciences Center, Denver, Colorado 80262
6 GI Cell Biology, Children's Hospital and Harvard
Medical School, and the Harvard Digestive Diseases Center,
Boston, MA 02115
* Corresponding author. E-mail address: wayne.lencer{at}tch.harvard.edu.
Cholera toxin (CT) travels from the plasma membrane of intestinal cells to the endoplasmic reticulum (ER) where a portion of the A subunit, the A1 chain, cross-es the membrane into the cytosol to cause disease. A related toxin, LTIIb, binds to intestinal cells but does not cause toxicity. Here, we show that the B-subunit of CT serves as a carrier for the A-subunit to the ER where disassembly occurs. The B-subunit binds to gangliosides in lipid rafts and travels with the ganglioside to the ER. In many cells, LTIIb follows a similar pathway, but in human intestinal cells it binds to a ganglioside that fails to associate with lipid rafts and it is sorted away from the retrograde pathway to the ER. Our results explain why LTIIb does not cause disease in humans and suggest that gangliosides with high affinity for lipid rafts may provide a general vehicle for the transport of toxins to the ER.
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