Claudins in lung diseases

Abstract

Tight junctions are the most apically localized part of the epithelial junctional complex. They regulate the permeability and polarity of cell layers and create compartments in cell membranes. Claudins are structural molecules of tight junctions. There are 27 claudins known, and expression of different claudins is responsible for changes in the electrolyte and solute permeability in cells layers. Studies have shown that claudins and tight junctions also protect multicellular organisms from infections and that some infectious agents may use claudins as targets to invade and weaken the host's defense. In neoplastic diseases, claudin expression may be up- or downregulated. Since their expression is associated with specific tumor types or with specific locations of tumors to a certain degree, they can, in a restricted sense, also be used as tumor markers. However, the regulation of claudin expression is complex involving growth factors and integrins, protein kinases, proto-oncogens and transcription factors. In this review, the significance of claudins is discussed in lung disease and development.

Figure 1

In an epithelial cell layer tight junctions (marked by green) regulate the permeability of solutes and ions through the paracellular space (a violet arrow pointing downwards). Thus they function as barriers of the paracellular space and also prevent pathogens from reaching the subepithelial tissues. Tight junction also takes part in determining the polarity of epithelial cells (red arrow). Since they are located in the apicolateral part of the cell membrane they separate the apical part of the cell membrane (red) from the lateral part (yellow) preventing membrane proteins from these parts of mixing up with each other (the fence function).

Figure 2

Interaction of claudins with scaffolding proteins ZO-1, ZO-2, ZO-3, MUPP1, cingulin and ZONAB in tight junctional structures. The arrows show interactions between specific molecules. If ZONAB is released from the association with ZO-1 it moves to the nucleus and binds to cyclin dependent kinase 4 (CDK 4) resulting in cellular proliferation. Apg-2 competes with ZONAB for the same binding site in ZO-1 thus affecting the binding of ZONAB to ZO-1 and releasing it to the nucleus. This is one example how tight junction proteins may influence the functions of the cell

Figure 3

Claudins are membranous proteins harbouring two extracellular loops (EL-1 and EL-2) and one small intracellular loop. The larger EL-1 loop regulates solute permeability and charge selectivity while the smaller EL-2 loop establishes contacts with the neigbouring cell. There are four transmembrane domains in claudin molecules. By the carboxyterminal part the claudin molecule attaches to the scaffolding proteins of the tight junctions.