Occludin
OCLN | |||
---|---|---|---|
Gene ontology | |||
Molecular function | |||
Cellular component | |||
Biological process | |||
Sources:Amigo / QuickGO |
Ensembl | |||||||||
---|---|---|---|---|---|---|---|---|---|
UniProt | |||||||||
RefSeq (mRNA) | |||||||||
RefSeq (protein) | |||||||||
Location (UCSC) | Chr 5: 69.49 – 69.56 Mb | Chr 13: 100.63 – 100.69 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
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.[5] 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,[6] and its redox-sensitive dimerization.[7][8] 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,[9] neurons and astrocytes,[10] oligodendrocytes,[11] dendritic cells,[12] monocytes/macrophages[13] lymphocytes,[14] and myocardium.[15] 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.[16] Furthermore, manipulation of occludin content in human cells is capable of influencing the expression of glucose transporters,[16] 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.[9]
Gene location
In humans is encoded by the OCLN
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.[20] The C-terminus also interacts with several cytoplasmic proteins of the junctional plaque and interacts with signaling molecules responsible for cell survival.[21] The N-terminus of occludin experimentally has been linked to involvement in tight junction sealing/barrier properties.[21] 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.[21]
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.[22] 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.[23]
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.[24]
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.[25] 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.[26]
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.
Interactions
Occludin has been shown to
References
- ^ a b c ENSG00000273814 GRCh38: Ensembl release 89: ENSG00000197822, ENSG00000273814 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021638 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 8276896.
- PMID 21235353.
- S2CID 23090886.
- )
- ^ PMID 26601824.
- PMID 10413597.
- PMID 17635647.
- PMID 11846220.
- PMID 26601824.
- S2CID 23713562.
- PMID 22108334.
- ^ PMID 28718701.
- PMID 8601611.
- ^ "Entrez Gene: OCLN occludin".
- ^ "OCLN occludin [Homo sapiens (human)] - Gene - NCBI".
- PMID 9265654.
- ^ PMID 15820558.
- PMID 33566640.
- PMID 11102513.
- PMID 20878095.
- PMID 22361748.
- PMID 16982755.
- S2CID 33062461.
- S2CID 20269381.
- S2CID 23928833.
- PMID 11950934.
- S2CID 23935899.
- PMID 12169098.
Further reading
- Furuse M, Itoh M, Hirase T, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S (December 1994). "Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions". The Journal of Cell Biology. 127 (6 Pt 1): 1617–26. PMID 7798316.
- Van Itallie CM, Anderson JM (May 1997). "Occludin confers adhesiveness when expressed in fibroblasts". Journal of Cell Science. 110 ( Pt 9) (9): 1113–21. PMID 9175707.
- Kimura Y, Shiozaki H, Hirao M, Maeno Y, Doki Y, Inoue M, et al. (July 1997). "Expression of occludin, tight-junction-associated protein, in human digestive tract". The American Journal of Pathology. 151 (1): 45–54. PMID 9212730.
- 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. PMID 9243183.
- Haskins J, Gu L, Wittchen ES, Hibbard J, Stevenson BR (April 1998). "ZO-3, a novel member of the MAGUK protein family found at the tight junction, interacts with ZO-1 and occludin". The Journal of Cell Biology. 141 (1): 199–208. PMID 9531559.
- 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. S2CID 36876977.
- 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. PMID 10581193.
- 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. PMID 10591624.
- Itoh M, Furuse M, Morita K, Kubota K, Saitou M, Tsukita S (December 1999). "Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins". The Journal of Cell Biology. 147 (6): 1351–63. PMID 10601346.
- Singh U, Van Itallie CM, Mitic LL, Anderson JM, McClane BA (June 2000). "CaCo-2 cells treated with Clostridium perfringens enterotoxin form multiple large complex species, one of which contains the tight junction protein occludin". The Journal of Biological Chemistry. 275 (24): 18407–17. S2CID 1240167.
- Marzioni D, Banita M, Felici A, Paradinas FJ, Newlands E, De Nictolis M, et al. (March 2001). "Expression of ZO-1 and occludin in normal human placenta and in hydatidiform moles". Molecular Human Reproduction. 7 (3): 279–85. PMID 11228248.
- Andreeva AY, Krause E, Müller EC, Blasig IE, Utepbergenov DI (October 2001). "Protein kinase C regulates the phosphorylation and cellular localization of occludin". The Journal of Biological Chemistry. 276 (42): 38480–6. S2CID 10856959.
- 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. S2CID 2704639.
- 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. PMID 11700038.
- Pummi K, Malminen M, Aho H, Karvonen SL, Peltonen J, Peltonen S (November 2001). "Epidermal tight junctions: ZO-1 and occludin are expressed in mature, developing, and affected skin and in vitro differentiating keratinocytes". The Journal of Investigative Dermatology. 117 (5): 1050–8. PMID 11710912.
- Traweger A, Fang D, Liu YC, Stelzhammer W, Krizbai IA, Fresser F, et al. (March 2002). "The tight junction-specific protein occludin is a functional target of the E3 ubiquitin-protein ligase itch". The Journal of Biological Chemistry. 277 (12): 10201–8. S2CID 34359119.
External links
- Vivian Tang. "OCCLUDIN in Focus". www.Zonapse.Net. Retrieved 2008-02-10.
- Vivian Tang. "Tight Junction Overview". www.Zonapse.Net. Retrieved 2008-02-10.
- GeneTests/NCBI/NIH/UW entry on Band-Like Calcification with Simplified Gyration and Polymicrogyria