Ganglioside GM1-mediated Transcytosis of Cholera Toxin Bypasses the Retrograde Pathway and Depends on the Structure of the Ceramide Domain

Abstract

Background: Mechanisms for intracellular lipid sorting remain poorly understood. Results: Polarized epithelial cells sort ganglioside GM1, the receptor for cholera toxin, into distinct retrograde and transcytotic pathways, provided that GM1 contains ceramide domains with short or unsaturated fatty acid chains. Conclusion: Sphingolipid sorting depends on ceramide structure, implicating a mechanism for lipid sorting by lipid shape. Significance: The results identify a lipid-sorting pathway across epithelial barriers with clinical applications.

Cytolethal Distending Toxin From Campylobacter jejuni Requires the Cytoskeleton for Toxic Activity

“…Some viruses or toxins use this route to reach the endoplasmic reticulum, such as the SV40 virus and cholera toxin. Given the structural similarity of the CDT and cholera toxin, this pathway may be involved in the entry of the C. jejuni CDT (50, 51). …”

Vibrio cholerae and Escherichia coli heat-labile enterotoxins and beyond

“…While an intact trans-Golgi network appears to be required [112], the Golgi apparatus may be dispensable for toxin function [113]. There are also studies indicating that CT might use a sorting pathway leading directly from the endosomal compartment to the ER [108], or even cross the cell all the way to the basolateral membrane by transcytosis, bypassing retrograde transport altogether (and breeching the intestinal barrier) [105].…”

“…Depending on the cell type, endocytosis can be either clathrin-dependent or clathrin-independent [103], where the clathrin-independent pathways differ in whether they are mediated by caveolin and dynamin, or not [104]. This diversity of mechanisms for endocytosis, reviewed by Chinnapen et al [100], might be explained by GM1 diversity, particularly by individual variations in the ceramide structure of the gangliosides [101,105]. Interference with the actin cytoskeleton has also been shown to decrease the transport of the CT from the plasma membrane, suggesting that an intact actin cytoskeleton is required for efficient transport of the CT [106].…”

Vaccination via Chloroplast Genetics: Affordable Protein Drugs for the Prevention and Treatment of Inherited or Infectious Human Diseases

“…Binding to GM1 causes retrograde trafficking of CTB through the cell and into the ER (5, 73). Alternatively, the entire CTB-GM1 complex may be transcytosed across the intestinal epithelium (113). Because functional CTB is pentameric, a hinge is engineered into the fusion protein to prevent steric hindrance and facilitate the formation of CTB pentamers (9, 29, 65, 72, 81, 117–119, 123, 135).…”