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Tight junctions: from simple barriers to multifunctional molecular gates

Key Points

  • Tight junctions are intercellular adhesion complexes in epithelia and endothelia that control paracellular permeability. This paracellular diffusion barrier is semipermeable: it is size- and charge-selective.

  • Paracellular ion permeability at tight junctions is largely determined by their claudin composition. Claudins are a family of transmembrane proteins that are thought to form gated ion-selective paracellular pores through the paracellular diffusion barrier.

  • Tight junctions form the border between the apical and basolateral cell surface domains in polarized epithelia, and support the maintenance of cell polarity by restricting intermixing of apical and basolateral transmembrane components.

  • Tight junctions are an integral component of the evolutionarily conserved signalling mechanisms that control epithelial-cell polarization and the formation of morphologically and functionally distinct apical domains.

  • Tight junctions form bidirectional signalling platforms that receive signals from the cell interior, which regulate their assembly and function, and that transduce signals to the cell interior to control cell proliferation, migration, differentiation and survival.

  • Tight junctions are part of an interconnected network of adhesion complexes that also includes adherens junctions and focal adhesions. These adhesion complexes crosstalk through direct protein–protein interactions as well as by transmitting signals to each other that influence their assembly and function.

Abstract

Epithelia and endothelia separate different tissue compartments and protect multicellular organisms from 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. Recent advances have broadened our understanding of the molecular architecture and cellular functions of tight junctions.

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Figure 1: The junctional complex and tight junctions.
Figure 2: Models of the structure and function of tight junctions.
Figure 3: Structure of claudins and intercellular pore formation.
Figure 4: Junction assembly and crosstalk between adhesion complexes.

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Acknowledgements

The authors are supported by the UK Medical Research Council, the UK Biotechnology and Biological Sciences Research Council, Fight for Sight and the Wellcome Trust.

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Glossary

Desmosomes

Adhesive structures, also known as maculae adhaerentes, formed from dense protein plaques of two adjacent cells, with associated intermediate filaments and transmembrane proteins, which belong to cadherin family.

MARVEL domain

A four-transmembrane helix module that has been identified in proteins of various families, many of which are associated with cholesterol-rich membrane microdomains.

Immunoglobulin-like domains

Protein domains consisting of a double-layer sandwich of seven to nine antiparallel β-stands arranged in two β-sheets.

Osmoregulation

A process used by cells and simple organisms to maintain fluid and electrolyte balance with their immediate environment.

Lipid micelles

Lipid molecules arranged in a spherical form in aqueous solutions as a result of the amphipathic nature of fatty acids, meaning that they contain a hydrophilic, polar head group and a long hydrophobic chain.

Patch clamp approach

An electrophysiology technique that allows the study of single and multiple ion channels in membranes.

Homology models

Comparative modelling of a protein through construction of an atomic-resolution model of the 'test' protein from its amino acid sequence and a resolved three-dimensional structure of a related homologous protein that is used as a template.

Brush border

The specialized apical membrane of absorptive epithelial cells, such as enterocytes. It is covered with regularly shaped microvilli: finger-like plasma membrane projections with a core formed by the actin cytoskeleton.

Focal adhesions

Large, dynamic protein complexes that link the cytoskeleton of a cell to the extracellular matrix.

Small GTPases

Small, monomeric proteins that are homologous to RAS. They exist in an inactive GDP-bound form and an active GTP-bound form in which they activate other signalling proteins.

Heterotrimeric GTPases

(Also called G proteins). These consist of three subunits: the GTP-binding α-subunit and the smaller β- and γ-subunits, which have regulatory and signalling functions.

Guanine nucleotide exchange factors

(GEFs). Proteins that activate monomeric GTPases by stimulating the dissociation of GDP, thereby permitting binding of GTP.

Hypertonic stress

A phenomenon experienced by cells and tissues when the extracellular-fluid osmolarity exceeds that of the intracellular fluid.

Stress fibres

Contractile actin bundles in non-muscle cells. They consist of actin microfilaments, myosin II and crosslinkers such as α-actinin.

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Zihni, C., Mills, C., Matter, K. et al. Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol 17, 564–580 (2016). https://doi.org/10.1038/nrm.2016.80

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