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Occludin is a transmembrane protein that regulates the permeability of epithelial and endothelial barriers. It was first identified in epithelial cells as a 65 kDa integral plasma-membrane protein localized at the tight junctions. Together with Claudins, and zonula occludens-1 (ZO-1), occludin has been considered a staple of tight junctions, and although it was shown to regulate the formation, maintenance, and function of tight junctions, its precise mechanism of action remained elusive and most of its actions were initially attributed to conformational changes following selective phosphorylation, and its redox-sensitive dimerization. However, mounting evidence demonstrated that occludin is not only present in epithelial/endothelial cells, but is also expressed in large quantities in cells that do not have tight junctions but have very active metabolism: pericytes, neurons and astrocytes, oligodendrocytes, dendritic cells, monocytes/macrophages lymphocytes, and myocardium. Recent work, using molecular modeling, supported by biochemical and live-cell experiments in human cells demonstrated that occludin is a NADH oxidase that influences critical aspects of cell metabolism like glucose uptake, ATP production and gene expression. Furthermore, manipulation of occludin content in human cells is capable of influencing the expression of glucose transporters, and the activation of transcription factors like NFkB, and histone deacetylases like sirtuins, which proved capable of diminishing HIV replication rates in infected human macrophages under laboratory conditions.
Gene location
In humans is encoded by the OCLNgene located on the long (q) arm of chromosome 5 at position q13.1. The canonical gene is 65,813 base pairs long, spanning base pairs 69,492,292 to 69,558,104. Its product is 522 amino acids long.
Protein structure
Occludin's structure can be broken down into 9 domains. These domains are separated into two groups. 5 of the domains are located intracellularly and extracellularly. These 5 domains are separated by the 4 transmembrane domains of the protein. The nine domains are as follows:
N-terminus domain (66 aa)
transmembrane domain 1 (23 aa)
extracellular loop 1 (46 aa)
transmembrane domain 2 (25 aa)
intracellular loop (10 aa)
transmembrane domain 3 (25 aa)
extracellular domain 2 (48 aa)
transmembrane domain 4 (22 aa)
C-terminus domain (257 aa)
The C-terminus domain has been shown experimentally to be required for correct assembly of tight junction barrier function. The C-terminus also interacts with several cytoplasmic proteins of the junctional plaque and interacts with signaling molecules responsible for cell survival. The N-terminus of occludin experimentally has been linked to involvement in tight junction sealing/barrier properties. The extracellular loops are thought to be involved in the regulation of paracellualr permeability and the second extracellular has been shown to be involved in the localization of occludin at the tight junction.
Function
Occludin is an important protein in tight junction function. Studies have shown that rather than being important in tight junction assembly, occludin is important in tight junction stability and barrier function. Indeed, MDCK cells lacking occludin and its homolog tricellulin exhibit less complex tight junction strand network and impaired barrier function. Furthermore, studies in which mice were deprived of occludin expression showed morphological stability in several epithelial tissues but also found chronic inflammation and hyperplasia in the gastric epithelium, calcification in the brain, testicular atrophy, loss of cytoplasmic granules in straited duct cells of salivary gland, and thinning of the compact bone. The phenotypical response of these mice to the lack of occludin suggest that the function of occludin is more complex than thought and requires more work.
Role in cancer
Occludin plays a critical role in maintaining the barrier properties of a tight junction. Thus, mutation or absence of occludin increases epithelial leakiness which is an important barrier in preventing metastasis of cancer. Loss of occludin or abnormal expression of occludin has been shown to cause increased invasion, reduced adhesion and significantly reduced tight junction function in breast cancer tissues. Furthermore, patients with metastatic disease displayed significantly lower levels of occludin suggesting that the loss of occludin and thereby loss of tight junction integrity is important in metastatic development of breast cancer.
Occludin also plays an important role in the apoptosis. The C-terminus of occludin is important in receiving and transmitting cell survival signals. In standard cells, loss or disruption of occludin and other tight junction proteins leads to initiation of apoptosis through extrinsic pathways. Studies involving high levels of expression of occludin in cancer cells have shown that occludin mitigates several important cancer proliferation properties. The presence of occludin decreased cellular invasiveness and motility, enhanced cellular sensitivity to apoptogenic factors and lowered tumorigenesis and metastasis of the cancer cells. Specifically, occludin has a strong inhibitory effect on Raf1-induced tumorigenesis. Still, the exact mechanism of how occludin prevents the progression of cancer is not known but it has been shown that cancer progression is linked to the loss of occludin or the silencing of the OCLN gene.
Disease linkage
Disruption of occludin regulation is an important aspect of a number of diseases. Strategies to prevent and/or reverse occludin downregulation may be an important therapeutic target. Mutation of occludin are thought to be a cause of band-like calcification with simple gyration and polymicrogyria (BLC-PMG). BLC-PMG is an autosomal recessive neurologic disorder.
Alexander JS, Dayton T, Davis C, Hill S, Jackson TH, Blaschuk O, et al. (December 1998). "Activated T-lymphocytes express occludin, a component of tight junctions". Inflammation. 22 (6): 573–82. doi:10.1023/a:1022310429868. PMID9824772. S2CID23713562.
Qiu L, Chen C, Ding G, Zhou Y, Zhang M (August 2011). "The effects of electromagnetic pulse on the protein levels of tight junction associated-proteins in the cerebral cortex, hippocampus, heart, lung, and testis of rats". Biomedical and Environmental Sciences. 24 (4): 438–44. Bibcode:2011BioES..24..438Q. doi:10.3967/0895-3988.2011.04.016. PMID22108334.
Van Itallie CM, Anderson JM (May 1997). "Occludin confers adhesiveness when expressed in fibroblasts". Journal of Cell Science. 110 ( Pt 9) (9): 1113–21. doi:10.1242/jcs.110.9.1113. PMID9175707.
Saitou M, Ando-Akatsuka Y, Itoh M, Furuse M, Inazawa J, Fujimoto K, Tsukita S (July 1997). "Mammalian occludin in epithelial cells: its expression and subcellular distribution". European Journal of Cell Biology. 73 (3): 222–31. PMID9243183.
Jiang WG, Martin TA, Matsumoto K, Nakamura T, Mansel RE (November 1999). "Hepatocyte growth factor/scatter factor decreases the expression of occludin and transendothelial resistance (TER) and increases paracellular permeability in human vascular endothelial cells". Journal of Cellular Physiology. 181 (2): 319–29. doi:10.1002/(SICI)1097-4652(199911)181:2<319::AID-JCP14>3.0.CO;2-S. PMID10497311. S2CID36876977.
Kojima T, Sawada N, Chiba H, Kokai Y, Yamamoto M, Urban M, et al. (December 1999). "Induction of tight junctions in human connexin 32 (hCx32)-transfected mouse hepatocytes: connexin 32 interacts with occludin". Biochemical and Biophysical Research Communications. 266 (1): 222–9. doi:10.1006/bbrc.1999.1778. PMID10581193.
Burns AR, Bowden RA, MacDonell SD, Walker DC, Odebunmi TO, Donnachie EM, et al. (January 2000). "Analysis of tight junctions during neutrophil transendothelial migration". Journal of Cell Science. 113 ( Pt 1) (1): 45–57. doi:10.1242/jcs.113.1.45. PMID10591624.
Papadopoulos MC, Saadoun S, Woodrow CJ, Davies DC, Costa-Martins P, Moss RF, et al. (October 2001). "Occludin expression in microvessels of neoplastic and non-neoplastic human brain". Neuropathology and Applied Neurobiology. 27 (5): 384–95. doi:10.1046/j.0305-1846.2001.00341.x. PMID11679090. S2CID2704639.
Schmidt A, Utepbergenov DI, Krause G, Blasig IE (November 2001). "Use of surface plasmon resonance for real-time analysis of the interaction of ZO-1 and occludin". Biochemical and Biophysical Research Communications. 288 (5): 1194–9. doi:10.1006/bbrc.2001.5914. PMID11700038.
