Modification of epithelial cell barrier permeability and intercellular junctions by Clostridium sordellii lethal toxins.
Clostridium sordellii lethal toxin (LT) is a glucosyltransferase which inactivates small GTPases from the Rho and Ras families. In the present work, we studied the effects of two variants, LT82 and LT9048, on the integrity of epithelial cell barrier using polarized MCCD (Mouse Cortical Collecting Duct) and MDCK (Madin-Darby Canine Kidney) cells. Our results demonstrate for the first time that LTs have very limited effects on tight junctions. In contrast, we show that both toxins modified the paracellular permeability within 2-4 h. Concomitantly LT82 and LT9048 induced a disorganization of basolateral actin filaments, without modifying apical actin. Both toxins mainly altered adherens junctions by removing E-cadherin-catenin complexes from the membrane to the cytosol. Similar effects on adherens junctions have been observed with other toxins, which directly or indirectly depolymerize actin. Thereby, Rac, a common substrate of both LTs, might play a central role in LT-dependent adherens junction alteration. Here, we show that adherens junction perturbation induced by LTs results neither from a direct effect of toxins on adherens junction proteins nor from an actin-independent Rac pathway, but rather from a Rac-dependent disorganization of basolateral actin cytoskeleton. This further supports that a dynamic equilibrium of cortical actin filaments is essential for functional E-cadherin organization in epithelia.
Boehm
Catherine
C
Unité des Bactéries anaérobies et Toxines, Institut Pasteur, 28 rue du Dr Roux, 75724, Paris Cedex 15, France.
Gibert
Maryse
M
Geny
Blandine
B
Popoff
Michel R
MR
Rodriguez
Pedro
P
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D022005:Adherens Junctions / Q000187:drug effects* / Q000648:ultrastructure; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology* / Q000633:toxicity; D015820:Cadherins / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects*; D016764:Cell Polarity; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D005614:Freeze Fracturing; D005964:Glucosyltransferases / Q000494:pharmacology*; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects; D019108:Tight Junctions / Q000187:drug effects* / Q000648:ultrastructure; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D001427:Bacterial Toxins; D015820:Cadherins; C072292:lethal toxin LT, Clostridium sordellii; D005964:Glucosyltransferases; D020741:rho GTP-Binding Proteins