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Multifunctional strands in tight junctions

Abstract

Tight junctions are one mode of cell–cell adhesion in epithelial and endothelial cellular sheets. They act as a primary barrier to the diffusion of solutes through the intercellular space, create a boundary between the apical and the basolateral plasma membrane domains, and recruit various cytoskeletal as well as signalling molecules at their cytoplasmic surface. New insights into the molecular architecture of tight junctions allow us to now discuss the structure and functions of this unique cell–cell adhesion apparatus in molecular terms.

Key Points

  • Tight junctions provide one type of cell-cell adhesion, acting as a barrier against solute diffusion through the intercellular space, providing boundaries between different membrane domains and recruiting cytoskeletal and signalling molecules.

  • Tight-junction morphology has been studied thoroughly by freeze-fracture replica electron microscopy, revealing that they are composed of sets of continuous intramembranous strands. Two models have been proposed to explain the chemical make-up of these strands - a 'protein model' and a 'lipid model'.

  • Integral membrane proteins that localize to tight junctions include occludin, claudins and junctional adhesion molecule (JAM).

  • Tight junctions vary in tightness. The number of strands correlates well with tightness, but the molecular mechanisms that regulate tight-junction strand number are not known. A possible role for different claudin types is discussed.

  • The existence of aqueous pores, taking open and closed states, has been proposed to exist within paired tight-junction strands. In addition to forming the backbone of tight-junction strands, claudins have been proposed to form extracellular aqueous pores.

  • Claudins bind numerous PDZ-containing proteins through their carboxyl termini. As a result, tight junction-strands are thought to have a magnetic bar function, recruiting cytoskeletal and signalling molecules to their cytoplasmic surface, which might contribute to signalling and polarization of the cell.

  • Tight-junction strands probably form a fence that limits diffusion of lipids and proteins between the apical and basolateral membrance domains.

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Figure 1: Junctional complex and tight junctions.
Figure 2: Structure of tight junctions.
Figure 3: Protein versus lipid models.
Figure 4: Integral membrane proteins localized at tight junctions.
Figure 5: Multiple functions of tight-junction strands.
Figure 6: PDZ-containing proteins localized at tight junctions.

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DATABASE LINKS

occludin

claudin-1

claudin-2

claudin-5

connexin

claudin-11

JAM

claudin-4

hereditary hypomagnesemia

claudin-16

claudin-3

ZO-1

ZO-2

ZO-3

SH3 domain

GUK domain

claudin-12

MAGI-1

MAGI-2

PTEN

PAR-3

PAR-6

cdc42

Rab3b

Rab13

Sec6

Sec8

tumour necrosis factor-α

interferon-γ

hereditary deafness

Glossary

EPITHELIAL CELLS

Closely packed cells, arranged in one or more layers, that cover the outer surfaces of the body or line any internal cavities or tubes (except the blood vessels, heart and serous cavities).

ENDOTHELIAL CELLS

Thin, flattened cells of mesoblastic origin that are arranged in a single layer lining the blood vessels and some body cavities, for example those of the heart.

MESOTHELIAL CELLS

Flat cells derived from mesoderm that are arranged in a single layer, found lining some body cavities.

ADHERENS JUNCTIONS

Cell–cell adhesive junctions that are linked to cytoskeletal filaments of the microfilament type.

DESMOSOMES

These patch-like intercellular junctions are found in vertebrate tissue, and are particularly abundant in tissues undergoing mechanical stress. The central plaque contains adhesion molecules, and represents an anchorage point for cytoskeletal filaments of the intermediate filament type.

TRANSCELLULAR TRANSPORT

Transport of macromolecules across a cell, including transport through channels, pumps and transporters, as well as transcytosis (endocytosis of a macromolecule at one side of a monolayer and exocytosis at the other side).

FREEZE-FRACTURE REPLICA ELECTRON MICROSCOPY

An electron-microscopic method that uses metal replicas to visualize the interior of cell membranes. This technique provides a convenient way to visualize the distribution of large integral membrane proteins as intramembranous particles in the plane of a membrane.

ANASTOMOSIS

Cross-connection between adjacent channels, tubes, fibres or other parts of a network.

P AND E FACE

When membranes are freeze-fractured, fracture planes run between the cytoplasmic and extracytoplasmic leaflets of plasma membranes, giving the P- or E-face images of membranes. The P (protoplasmic) face is the inner leaflet viewed from the outside, whereas the E (extracytoplasmic) face is the outer leaflet viewed from the inside.

IMMUNO-REPLICA ELECTRON MICROSCOPY

A form of electron microscopy, combining freeze-fracture replica electron microscopy and immune labelling of proteins.

SERTOLI CELLS

A supporting cell of the mammalian testis that surrounds and nourishes developing sperm cells.

VISCERAL ENDODERM

Cells that delineate the yolk sac cavity together with parietal endoderm cells in the egg cylinder stage of the mammalian embryo.

L FIBROBLASTS

A mouse fibroblast line derived from connective tissue that does not show adhesion activity.

OLIGODENDROCYTES

A type of glial cell that forms and supports the myelin sheath around axons in the central nervous system of vertebrates.

EXTRAVASATE

Let or force out something from a vessel that naturally contains it.

MONOCYTES

Large leukocyte of the mononuclear phagocyte system found in bone marrow and the bloodstream. Monocytes are derived from pluripotent stem cells and become macrophages when they enter the tissues.

TRANSEPITHELIAL ELECTRIC RESISTANCE

Electric resistance across epithelial sheets, measured across the apical–basolateral axis of the cell.

MYELIN SHEATH

The sheath that surrounds the axons of vertebrate nerves to prevent the leakage of electric current. It is formed by Schwann cells in peripheral nerves and by oligodendrocytes in the central nervous system. These cells wrap up to 100 concentric layers of their plasma membrane in a tight spiral around the axons.

LIMB OF HENLE

U-shaped part of a nephron lying in the renal medulla. It comprises a thin descending tubule and an ascending tubule formed of both a thin and a thick segment. It has a role in the selective reabsorption of fluid and solutes.

HYPERPLASIA

The increase in the size of a tissue or organ, resulting from an increase in the total number of cells present. The part that is affected retains its normal form.

GAP JUNCTION

A junction between two cells consisting of pores that allow passage of molecules (up to 9 kDa).

PDZ DOMAIN

Protein–protein interaction domain first described in the proteins PSD-95, DLG and ZO-1.

POSTSYNAPTIC DENSITY

Higher-order protein structure present in postsynaptic membranes that functions to concentrate neurotransmitter receptors.

INTEGRINS

A large family of heterodimeric transmembrane proteins that act as receptors for cell-adhesion molecules.

CADHERINS

Calcium-dependent adhesion molecules that mediate homophilic adhesions. There are several subfamilies of cadherin.

GLYCOSPHINGOLIPIDS

Any compound containing residues of a sphingoid and at least one monosaccharide.

SPHINGOMYELIN

Any of a class of phospholipids in which the amino group of sphingosine is in amide linkage with a fatty acid, and the terminal hydroxyl group of sphingosine is esterified to phosphorylcholine.

HETEROTRIMERIC G PROTEINS

Components of receptor-mediated activation or inhibition of adenylyl cyclase and other second messenger systems.

MITOGEN-ACTIVATED PROTEIN KINASE CASCADE

Signalling cascade that relays signals from the plasma membrane to the nucleus. MAPKs, which represent the first step in the pathway, are activated by a wide range of proliferation- or differentiation-inducing signals.

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Tsukita, S., Furuse, M. & Itoh, M. Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol 2, 285–293 (2001). https://doi.org/10.1038/35067088

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