Claudine

Claudins (from the Latin claudere - to close) belong to a superfamily that currently consists of 27 small transmembrane proteins in humans/mammals (claudin-1/ claudin- 27) and 67 in fish. Claudins are highly conserved (already detectable in nematodes) transmembrane proteins. They are an important component of the cell junctions found in epithelia (see cell contacts below), the so-called tight junctions. Remarkably, the coding genes are not found in a cluster, but are distributed on different chromosomes.

Claudin-1 is expressed in various neurogenic tumors and serves as a diagnostic marker.

Isoform 2 of claudin-18, CLDN 18.2, is physiologically expressed in the epithelial cells of the gastric mucosa. Claudin 18.2 is overexpressed in a large number of tumor cells. This is also the case in gastric, pancreatic and oesophageal cancer as well as in non-small cell lung cancer (NSCLC) and its metastases. Claudin 18.2 is a target protein for targeted tumor therapy of various solid tumors (see claudiximab below).

Individual claudin proteins are generally classified as either barrier-forming or pore-forming (channel-forming) claudins, depending on whether their expression increases or decreases permeability. For example, overexpression of claudin-1 and 4 in MDCK epithelial cells leads to decreased permeability (Van Itallie C et al. 2001).

A decrease in claudin-1 expression in human skin keratinocytes leads to increased epithelial permeability, indicating a disruption of barrier function (Yamamoto T et al. 2008; De Benedetto A et al. 2011). Therefore, claudin-1 and claudin-4 are classified as barrier claudins. Other barrier claudins are claudins 5, 6, 8, 9, 11, 15 and 19. Overexpression of claudin-6 also downregulates the expression of other claudins, suggesting a negative feedback loop between existing claudins and subsequent claudin expression. In mice overexpressing claudin-6, the epidermis also shows abnormal expression of differentiation markers such as keratin 1, filaggrin, loricrin and involucrin (Turksen K et al. 2002).

Interleukin-33 reduces the expression of filaggrin and claudin-1, which leads to a reduction in the barrier function of the skin. However, the destruction of the barrier leads to percutaneous exposure to allergens or the release of interleukin-33 (IL-33). Thus, IL-33 is a common target for the itch-scratch cycle of atopic dermatitis (Imai Y 2019).

Remarkably, filaggrin gene knockdown leads to a reduced level not only of keratin 10 but also of the TJ proteins ZO-1, claudin-1 and occludin. In parallel, there is an increase in cysteine proteases, which in turn can degrade TJ proteins (Wang et al. 2017).

In addition to their functions and expression in epithelial tissues, claudins have also been identified in tissue-specific distributions in the endothelium. For example, human brain and mouse endothelial cells express claudins 3, 5 and 12, while kidney endothelial cells express claudins 5 and 15.

1. De Benedetto A et al. (2011) Tight junction defects in patients with atopic dermatitis. J Allergy Clin Immunol 127: 773-786.
2. Hayashi T et al. (2013) Hybrid schwannoma/perineurioma of the spinal nerve: multifocal occurrence, and recurrence as an intraneural perineurioma. Pathol Int 63:368-373.
3. Imai Y (2019) Interleukin-33 in atopic dermatitis. J Dermatol Sci 96:2-7.
4. Turksen K et al (2002) Permeability barrier dysfunction in transgenic mice overexpressing claudin 6. Development 129: 1775-1784.
5. Yamamoto T et al. (2008) Effect of RNA interference of tight junction-related molecules on intercellular barrier function in cultured human keratinocytes. Arch Dermatol Res 300: 517-524.
6. Wang XW et al. (2017) Deficiency of filaggrin regulates endogenous cysteine protease activity, leading to impaired skin barrier function. Clin Exp Dermatol 42: 622-631.