Tight junctions: from simple barriers to multifunctional molecular gates

Abstract

Main body of text: 5983 words 2Epithelia and endothelia separate different tissue compartments and protect multicellular organisms form the outside world. This requires the formation of tight junctions, selective gates that control paracellular diffusion of ions and solutes. Tight junctions also form the border between the apical and basolateral plasma membrane domains and are linked to the machinery that controls apicobasal polarization. Additionally, signalling networks that guide diverse cell behaviours and functions are connected to tight junctions, transmitting information to and from the cytoskeleton, nucleus and different cell adhesion complexes. Here, we discuss recent advances in our understanding of the molecular architecture and cellular functions of tight junctions.Microscopists in the 19 th century described the paracellular space between neighbouring cells within an epithelial sheet to be sealed by a "terminal bar", a structure later resolved by electron microscopy into a composite of distinct cell-cell junctions that is now called the epithelial junctional complex and is formed by tight junctions, adherens junctions and desmosomes 1,2 . As the former two junctions are more tightly associated and often reside at the apical end of the lateral membrane, they are often referred to as the apical junctional complex (however, in endothelia, tight junctions and adherens junctions can be intercalated) (Fig. 1). Tight junctions are essential for barrier formation, and their primary physiological role is to function as paracellular gates that restrict diffusion on the basis of size and charge. Selective paracellular diffusion is an essential process for the maintenance of homoeostasis in organs and tissues. Tight junctions have long been the most enigmatic of all adhesion complexes and eluded a detailed molecular and functional analysis due to their complex architecture. Recent years have witnessed the identification of a large array of components associated with tight junctions implicating these junctions in an unexpected range of different functions, thereby challenging the traditional model, in which tight junctions are considered a simple diffusion barrier formed by a rigid molecular complex. In line with these various functions, mutations in genes encoding tight junction proteins have been linked to a range of inherited human diseases. Additionally, tight junction components are known to be targeted by a number of pathogenic bacteria and viruses, which hijack tight junction proteins to enter and infect cells, or target junctional signalling mechanisms to cross tissue barriers. Although tight junctions are a vertebrate junction, many of their components and functions are evolutionarily conserved (Box 1).The main purpose of this review is to examine the recent advances in the unravelling of the molecular architecture of tight junctions and understanding their functions. We will discuss recent exciting insights into how tight junctions function as signalling platforms that guide cell behaviour and differen...

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…They control paracellular movements and guarantee the cell polarity by impeding the diffusion of transmembrane proteins between the apical and the basolateral membrane domains. Intercellular tight junctions are formed by a combination of transmembrane proteins, namely claudins and occludin, which interact with the F-actin cytoskeleton through various scaffold cytoplasmic proteins [172]. Claudins, which are actually responsible for controlling the paracellular permeability, are of two types.…”

Tuning Collective Cell Migration by Cell–Cell Junction Regulation

“…TJs are indispensable for creating a barrier between different regions of the body, and their main role is to function as paracellular gates that restrict diffusion on the basis of size and charge. TJs are composed of transmembrane proteins (claudin, occludin, tricellulin, and marveld3) that seem sufficient to trigger at least some of the aspects required in TJ formation, including mechanical junction stability and apicobasal polarity of connected cells (Zihni et al 2016). Other TJ transmembrane adhesion proteins comprise the junctional adhesion molecules (JAMs), which enhance TJ stability and turnover (Ebnet et al 2004;Luissint et al 2014).…”

Claudin-3 and occludin content in the glands of colonic mucosa devoid from fecal stream submitted to topical intervention with oil extract of Curcuma longa

“…Among the claudins that tighten the paracellular barrier of the gastrointestinal tract are claudin-1, -3, -4, -5, and -8. These proteins have their highest expression in the colon and it follows that the colon has the highest epithelial resistance 23,24 . The exact barrier function of occludin is not completely understood but studies have shown that it has to be present in the TJs strands and to have a functional role in the connection between the intracellular filaments forming proteins claudin and the cytoskeleton 24 .…”

“…These proteins have their highest expression in the colon and it follows that the colon has the highest epithelial resistance 23,24 . The exact barrier function of occludin is not completely understood but studies have shown that it has to be present in the TJs strands and to have a functional role in the connection between the intracellular filaments forming proteins claudin and the cytoskeleton 24 . Defective intestinal epithelial TJs barrier has been postulated to be an important pathogenic mechanism leading to the increase in intestinal antigenic penetration and subsequent development of intestinal inflammation 22 .…”