Occludins

Occludin (from the Latin occludere) was first described in 1993 by the research group led by Mikio Furuse and Shoichiro Tsukita. This research group fractionated extracts from chicken liver and found a protein with a molar mass of 55.9 kDa, which consisted of 504 amino acids.

Occludins are transmembrane proteins which, together with the proteins of the claudin family, are involved in the formation of tight junctions, which occur in epithelial cells of all vertebrates. Tight junctions close the intercellular spaces in the epithelia and protect the organism from both dehydration and external influences (e.g. from the acidic contents of the stomach with a pH between 1 and 2).

Occludins are transmembrane proteins with four transmembrane domains, which is why they can be divided into five different domains (each interrupted by a transmembrane domain), which are called A-E. Thus, all proteins of this family have two extracellular loops, which are both about the same size (45 amino acids each), a short intracellular loop connecting the two extracellular loops, and two long chains at the N- and C-terminus. The two extracellular loops are necessary to maintain function (cell-cell junction) and one of them seems to play a role in the localization of occludin in the tight junctions. The E-domain is localized in the cytoplasm and is necessary to bind the protein ZO-1.

To date, five different types of occludin have been found (type I to IV) (Mankertz J etal. 2002) as well as occludin 1B, which result from different splicing of the mRNA. This possibly indicates that several proteins with similar properties (as in the claudins) form an occludin protein family.

Occludins serve as an output receptor for GTPase signaling, and increased phosphorylation of occludin proteins decreases TJ permeability (Harhaj NS et al. 2004).

In a study with mice, Simon Bamforth and colleagues showed that a mutated occludin lacking the N-terminus and the extracellular domains is still transported to the tight junctions, but can no longer perform its function there and the tight junctions become more permeable.

The interaction partners of occludins are ZO-1, ZO-2 and the protein ZO-3 . It is assumed that ZO-1 binds occludins directly and connects them to the actin cytoskeleton. Interactions of occludins with other proteins have also been found.

In addition, occludins are most likely phosphorylated by protein kinase C (PKC), which then alters the distribution and function of the protein in the cell.

Furthermore, Ras-like G proteins such as RhoA and Rac-1 may play a role in the regulation of occludins, as well as cytokines in the regulatory process (Gemma J et al. 2005).

1. Gemma J et al. (2005) Occludin: Structure, function and regulation. In: Adv Drug Deliv Rev. 57: 883-917.
2. Furuse M et al. (1993) Occludin a novel integral membrane protein localizing at tight junctions. In: J Cell Biol 123: 1777-1788.
3. Bamforth SD et al. (1999) A dominant mutant of occludin disrupts tight junction structure and function. J Cell Sci 112: 1879-1888.
4. Harhaj NS et al. (2004) Regulation of tight junctions and loss of barrier function in pathophysiology. Int J Biochem Cell Biol 36: 1206-1237.
5. Kuo WT et al. (2022) Tight junction proteins occludin and ZO-1 as regulators of epithelial proliferation and survival. Ann N Y Acad Sci 1514:21-33.
6. Kuo WT et al. (2019) Inflammation-induced Occludin Downregulation Limits Epithelial Apoptosis by Suppressing Caspase-3 Expression. Gastroenterology 157:1323-1337.
7. Mankertz J etal. (2002) Gene expression of the tight junction protein occludin includes differential splicing and alternative promoter usage. Biochem Biophys Res Commun 298: 657-66
8. Muresan Z et al. (2000) Occludin 1B, a variant of the tight junction protein occludin. Mol Biol Cell 11: 627-634.

9. Raleigh DR et al. (2010) Tight junction-associated MARVEL proteins marveld3, tricellulin, and occludin have distinct but overlapping functions. Mol Biol Cell 21: 1200-1213.