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Vol. 14, Issue 12, 4783-4793, December 2003
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* GI Cell Biology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115;
|| Harvard Digestive Diseases Center, Boston, Massachusetts 02115;
Department of Bacteriology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama, 700-8558, and Precursory Research for Embryonic Science and Technology, Japan Science and Technology Corporation, Saitama Prefecture 332-0012 Japan;
Cell Biology, Harvard Medical School, Boston, Massachusetts 02115; and
Department of Microbiology, University of Colorado Health Sciences Center, Denver, Colorado 80262
Submitted June 2, 2003;
Revised July 9, 2003;
Accepted August 7, 2003
Monitoring Editor: Pamela Silver
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, crosses 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.
Abbreviations used: CT, cholera toxin; LTIIb, E. coli heat-labile toxin type II.
¶ Corresponding author. E-mail address: wayne.lencer{at}tch.harvard.edu.
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