Ochratoxin A displaces claudins from detergent resistant membrane microdomains.
Ochratoxin A (OchA) is a food-borne mycotoxin with multiple effects in vivo. Previously, we have demonstrated that the toxin can significantly impair the barrier function of the gut epithelial cell line, Caco-2. Barrier disruption involved loss of claudins 3 and 4, but not claudin 1 from the tight junction complex. In this study, we demonstrate for the first time, that OchA is able to remove claudins 3 and 4 from the detergent insoluble membrane microdomains associated with the tight junctions. However, cholesterol distribution within the microdomain was unaffected by the toxin. In addition, the thiol antioxidant, N-acetyl cysteine, preserved the microdomain localisation of claudins and also the barrier function of Caco-2 cells. This work suggests that OchA-mediated barrier toxicity is due to removal of claudins from detergent insoluble membrane microdomains. Moreover, loss of microdomain association may be due to oxidative events.
Lambert
Daniel
D
Section of Gastrointestinal Sciences, School of Medicine, University of Manchester, Stopford Building, Oxford Road, Manchester, UK.
Padfield
Philip J
PJ
McLaughlin
John
J
Cannell
Stephanie
S
O'Neill
Catherine A
CA
D018938:Caco-2 Cells; D003902:Detergents / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D009793:Ochratoxins / Q000008:administration & dosage*; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism*
D003902:Detergents; D008565:Membrane Proteins; D009793:Ochratoxins; C025589:ochratoxin A