A key claudin extracellular loop domain is critical for epithelial barrier integrity

TY - JOUR

T1 - A key claudin extracellular loop domain is critical for epithelial barrier integrity

AU - Mrsny, Randall J

AU - Brown, G T

AU - Gerner-Smidt, K

AU - Buret, A G

AU - Meddings, J B

AU - Quan, C

AU - Koval, M

AU - Nusrat, A

PY - 2008/4

Y1 - 2008/4

N2 - Intercellular tight junctions (TJs) regulate epithelial barrier properties. Claudius are major structural constituents of TJs and belong to a large family of tetraspanning membrane proteins that have two predicted extracellular loops (ELs). Given that claudin-1 is widely expressed in epithelia, we further defined the role of its EL domains in determining TJ function. The effects of several claudin-1 EL mimetic peptides on epithelial barrier structure and function were examined. incubation of model human intestinal epithelial cells with a 27-amino acid peptide corresponding to a portion of the first EL domain (Cldn-1(53-80)) reversibly interfered with epithelial barrier function by inducing the rearrangement of key TJ proteins: occludin, claudin-1, junctional adhesion molecule-A, and zonula occludens-1. Cldn-1(53-80) associated with both claudin-1 and occludin, suggesting both the direct interference with the ability of these proteins to assemble into functional TJs and their close interaction under physiological conditions. These effects were specific for Cldn-1(53-80), because peptides corresponding to other claudin-1 EL domains failed to influence TJ function. Furthermore, the oral administration of Cldn-1(53-80) to rats increased paracellular gastric permeability. Thus, the identification of a critical claudin-1 EL motif, Cldn-1(53-80), capable of regulating TJ structure and function, offers a useful adjunct to treatments that require drug delivery across an epithelial barrier.

AB - Intercellular tight junctions (TJs) regulate epithelial barrier properties. Claudius are major structural constituents of TJs and belong to a large family of tetraspanning membrane proteins that have two predicted extracellular loops (ELs). Given that claudin-1 is widely expressed in epithelia, we further defined the role of its EL domains in determining TJ function. The effects of several claudin-1 EL mimetic peptides on epithelial barrier structure and function were examined. incubation of model human intestinal epithelial cells with a 27-amino acid peptide corresponding to a portion of the first EL domain (Cldn-1(53-80)) reversibly interfered with epithelial barrier function by inducing the rearrangement of key TJ proteins: occludin, claudin-1, junctional adhesion molecule-A, and zonula occludens-1. Cldn-1(53-80) associated with both claudin-1 and occludin, suggesting both the direct interference with the ability of these proteins to assemble into functional TJs and their close interaction under physiological conditions. These effects were specific for Cldn-1(53-80), because peptides corresponding to other claudin-1 EL domains failed to influence TJ function. Furthermore, the oral administration of Cldn-1(53-80) to rats increased paracellular gastric permeability. Thus, the identification of a critical claudin-1 EL motif, Cldn-1(53-80), capable of regulating TJ structure and function, offers a useful adjunct to treatments that require drug delivery across an epithelial barrier.

UR - http://www.scopus.com/inward/record.url?scp=42049095894&partnerID=8YFLogxK

UR - http://dx.doi.org/10.2353/ajpath.2008.070698

U2 - 10.2353/ajpath.2008.070698

DO - 10.2353/ajpath.2008.070698

M3 - Article

VL - 172

SP - 905

EP - 915

JO - American Journal Of Pathology

JF - American Journal Of Pathology

SN - 0002-9440

IS - 4

ER -