The epithelial barrier and beyond: Claudins as amplifiers of physiological organ functions

Abstract

Epithelial cell layers are interconnected by a meshwork of tight junction (TJ) protein strands, which are localized within apicolateral membranes. The proteins that form TJs are regarded to provide a static barrier, determining epithelial properties. However, recent findings in the field of barriology suggest that TJs contribute to more physiological aspects than indicated by the sum of the qualities of the single TJ proteins. Generally, TJs exhibit four major functions: (i) a "gate function," defining transepithelial permeability (i.e., barrier) properties, (ii) a "fence function" determining epithelial cell polarity, (iii) a "signaling function," affecting regulatory pathways, and (iv) a "stabilizing function," maintaining the integrity of the epithelium. This review presents a critical view on how the efficacy of physiological processes in epithelia and thus organ function might be improved by changes in the expression of claudins, the latter representing the largest and most variable family of TJ proteins. Major focus is set on (i) the coordinated regulation of transport and barrier in the intestine, (ii) the role of TJs in defining the route for antigen uptake and presentation in intestinal Peyer's patches, and (iii) the TJ function in mammary glands in response to milk accumulation, which represent impressive examples to highlight the amplification of epithelial functions by TJ proteins. © 2017 IUBMB Life, 69(5):290-296, 2017.

Molecular Characterization of Barrier Properties in Follicle-Associated Epithelium of Porcine Peyer's Patches Reveals Major Sealing Function of Claudin-4

“…Apart from claudin-4, a number of other intestinal claudins are known to be susceptible to barrier effectors and perturbation, namely claudin-1 and claudin-2 (Amasheh et al, 2009 , 2010 ), claudin-3 and claudin-4 (Markov et al, 2014 ), claudin-5 and claudin-8 (Dittmann et al, 2014 ; Barmeyer et al, 2017 ). Although the interplay of these TJ proteins with transport function and signaling might still be worth considering with regard to porcine PP FAE (Markov et al, 2015 , 2017 ), no differences of these claudins with respect to their localization and expression levels have been observed, at least under the non-challenging conditions of the current study.…”

“…Organized as bands surrounding the upper part of epithelial cells, TJs are the structural correlate of intestinal barrier function (Martinez-Palomo and Erlij, 1975 ). In recent years, our understanding of the molecular basis of epithelial barrier function has greatly advanced (Markov et al, 2015 , 2017 ; Suzuki et al, 2017 ). TJ strands are composed mainly of tetraspan transmembrane proteins of the claudin family (Furuse et al, 1998 ) and determine the paracellular movement of ions, water, and small molecules (Amasheh et al, 2002 ; Rosenthal et al, 2010 ).…”

“…Although these general structural properties of PP have been described, information on the Para cellular pathway of the PP epithelium remained limited until our previous study showing the differential distribution of the barrier function in correlation with the expression and localization of tight junction (TJ) proteins in rat PP FAE (Markov et al, 2016 ). In this context, the functional contribution of single TJ proteins to epithelial barrier physiology has been reviewed in detail recently, highlighting the special role of claudins as a main TJ component (Markov et al, 2015 , 2017 ).…”

Tight Junction Proteins and the Biology of Hepatobiliary Disease

“…However, in both cases, TJs build a regulatory semipermeable gate that enables selective paracellular diffusion depending on the size and charge of the corresponding molecule [1]. Moreover, TJs form an intramembrane barrier (also referred to as ''fence function''), that restricts exchange between the cells' apical and basolateral surfaces [13]. However, whether the fence function of TJs is critical or not for the establishment of a polarized phenotype has been a matter of debate, taking into account that it has been observed how epithelial cells are able to polarize in the absence of cell-cell junctions [14,15].…”

Xenopus oocytes as a heterologous expression system for analysis of tight junction proteins

“…Among the models used for functional TJ protein analysis, knockout models (7) and overexpression models (8) have provided major insights into the functional contribution of single TJ proteins to organ function. Moreover, interaction analysis has gained importance, with the molecular assembly of cldns having been successfully addressed (9, 10). However, a limiting aspect in the studies focusing on the interaction and functional contribution of cldns remains their background expression in all epithelial models; this problem has been experimentally avoided in a pioneering approach by using nonepithelial cells for TJ protein analysis, namely mouse L‐fibroblasts (11).…”