Occludin

Last updated
OCLN
Occludin.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases OCLN , BLCPMG, PPP1R115, occludin, PTORCH1
External IDs OMIM: 602876 MGI: 106183 HomoloGene: 1905 GeneCards: OCLN
Orthologs
SpeciesHumanMouse
Entrez

100506658

18260

Ensembl

ENSG00000197822
ENSG00000273814

ENSMUSG00000021638

UniProt

Q16625

Q61146

RefSeq (mRNA)

NM_002538
NM_001205254
NM_001205255

NM_008756
NM_001360536
NM_001360537
NM_001360538
NM_001360539

Contents

RefSeq (protein)

NP_001192183
NP_001192184
NP_002529

NP_032782
NP_001347465
NP_001347466
NP_001347467
NP_001347468

Location (UCSC) Chr 5: 69.49 – 69.56 Mb Chr 13: 100.63 – 100.69 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Diagram of Tight junction. Cellular tight junction-en.svg
Diagram of Tight junction.

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 gene [17] [18] 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. [19] 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:

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 interact with Tight junction protein 2, [27] [28] [29] YES1 [30] and Tight junction protein 1 (ZO-1). [31] [32]

Related Research Articles

<span class="mw-page-title-main">Tight junction</span> Structure preventing inter-cell leakage

Tight junctions, also known as occluding junctions or zonulae occludentes, are multiprotein junctional complexes whose canonical function is to prevent leakage of solutes and water and seals between the epithelial cells. They also play a critical role maintaining the structure and permeability of endothelial cells. Tight junctions may also serve as leaky pathways by forming selective channels for small cations, anions, or water. The corresponding junctions that occur in invertebrates are septate junctions.

<span class="mw-page-title-main">Claudin</span> Group of proteins forming tight junctions between cells

Claudins are a family of proteins which, along with occludin, are the most important components of the tight junctions. Tight junctions establish the paracellular barrier that controls the flow of molecules in the intercellular space between the cells of an epithelium. They have four transmembrane domains, with the N-terminus and the C-terminus in the cytoplasm.

<span class="mw-page-title-main">Tight junction protein 1</span> Protein found in humans

Zonula occludens-1 ZO-1, also known as Tight junction protein-1 is a 220-kD peripheral membrane protein that is encoded by the TJP1 gene in humans. It belongs to the family of zonula occludens proteins, which are tight junction-associated proteins and of which, ZO-1 is the first to be cloned. It was first isolated in 1986 by Stevenson and Goodenough using a monoclonal antibody raised in rodent liver to recognise a 225-kD polypeptide in whole liver homogenates and in tight junction-enriched membrane fractions. It has a role as a scaffold protein which cross-links and anchors Tight Junction (TJ) strand proteins, which are fibril-like structures within the lipid bilayer, to the actin cytoskeleton.

<span class="mw-page-title-main">CLDN1</span> Protein-coding gene in the species Homo sapiens

Claudin-1 is a protein that in humans is encoded by the CLDN1 gene. It belongs to the group of claudins.

<span class="mw-page-title-main">Tight junction protein 2</span> Protein found in humans

Tight junction protein ZO-2 is a protein that in humans is encoded by the TJP2 gene.

<span class="mw-page-title-main">CLDN4</span> Protein-coding gene in the species Homo sapiens

Claudin 4, also known as CLDN4, is a protein which in humans is encoded by the CLDN4 gene. It belongs to the group of claudins.

<span class="mw-page-title-main">F11 receptor</span> Protein-coding gene in the species Homo sapiens

Junctional adhesion molecule A is a protein that in humans is encoded by the F11R gene. It has also been designated as CD321.

<span class="mw-page-title-main">CLDN5</span> Protein-coding gene in the species Homo sapiens

Claudin-5 is a protein that in humans is encoded by the CLDN5 gene. It belongs to the group of claudins.

<span class="mw-page-title-main">CLDN3</span> Protein-coding gene in the species Homo sapiens

Claudin 3, also known as CLDN3, is a protein which in humans is encoded by the CLDN3 gene. It is a member of the claudin protein family.

<span class="mw-page-title-main">CLDN7</span> Protein-coding gene in humans

Claudin-7 is a protein that in humans is encoded by the CLDN7 gene. It belongs to the group of claudins.

<span class="mw-page-title-main">CLDN6</span> Protein-coding gene in the species Homo sapiens

Claudin-6 is a protein that in humans is encoded by the CLDN6 gene. It belongs to the group of claudins. The knockout mice of mouse homolog exhibit no phenotype, indicating that claudin-6 is dispensable for normal development and homeostasis.

<span class="mw-page-title-main">CLDN2</span> Protein-coding gene in humans

Claudin-2 is a protein that in humans is encoded by the CLDN2 gene. It belongs to the group of claudins.

<span class="mw-page-title-main">CLDN12</span> Protein-coding gene in the species Homo sapiens

Claudin-12 is a protein that in humans is encoded by the CLDN12 gene. It belongs to the group of claudins.

<span class="mw-page-title-main">CLDN8</span> Protein-coding gene in the species Homo sapiens

Claudin-8 is a protein that in humans is encoded by the CLDN8 gene. It belongs to the group of claudins.

<span class="mw-page-title-main">CLDN14</span> Protein-coding gene in the species Homo sapiens

Claudin-14 is a protein that in humans is encoded by the CLDN14 gene. It belongs to a related family of proteins called claudins.

<span class="mw-page-title-main">Cingulin</span> Protein found in humans

Cingulin is a cytosolic protein encoded by the CGN gene in humans localized at tight junctions (TJs) of vertebrate epithelial and endothelial cells.

<span class="mw-page-title-main">CLDN18</span> Protein-coding gene in the species Homo sapiens

Claudin-18 is a protein that in humans is encoded by the CLDN18 gene. It belongs to the group of claudins.

<span class="mw-page-title-main">TJP3</span> Protein-coding gene in the species Homo sapiens

Tight junction protein ZO-3 is a protein that in humans is encoded by the TJP3 gene.

Tight junction proteins are molecules situated at the tight junctions of epithelial, endothelial and myelinated cells. This multiprotein junctional complex has a regulatory function in passage of ions, water and solutes through the paracellular pathway. It can also coordinate the motion of lipids and proteins between the apical and basolateral surfaces of the plasma membrane. Thereby tight junction conducts signaling molecules, that influence the differentiation, proliferation and polarity of cells. So tight junction plays a key role in maintenance of osmotic balance and trans-cellular transport of tissue specific molecules. Nowadays is known more than 40 different proteins, that are involved in these selective TJ channels.

<span class="mw-page-title-main">OCEL1</span> Protein-coding gene in the species Homo sapiens

OCEL1, also called Occludin//ELL Domain Containing 1, is a protein encoding gene located at chromosome 19p13.11 in the human genome. Other aliases for the gene include FLJ22709, FWP009, and S863-9. The function of OCEL1 has not yet been identified.

References

  1. 1 2 3 ENSG00000273814 GRCh38: Ensembl release 89: ENSG00000197822, ENSG00000273814 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000021638 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S (December 1993). "Occludin: a novel integral membrane protein localizing at tight junctions". The Journal of Cell Biology. 123 (6 Pt 2): 1777–88. doi:10.1083/jcb.123.6.1777. PMC   2290891 . PMID   8276896.
  6. ↑ Blasig IE, Bellmann C, Cording J, Del Vecchio G, Zwanziger D, Huber O, Haseloff RF (September 2011). "Occludin protein family: oxidative stress and reducing conditions". Antioxidants & Redox Signaling. 15 (5): 1195–219. doi:10.1089/ars.2010.3542. PMID   21235353.
  7. ↑ Walter JK, Castro V, Voss M, Gast K, Rueckert C, Piontek J, Blasig IE (November 2009). "Redox-sensitivity of the dimerization of occludin". Cellular and Molecular Life Sciences. 66 (22): 3655–62. doi:10.1007/s00018-009-0150-z. PMID   19756380. S2CID   23090886.
  8. ↑ Villela C, Manuel V (2011). "The interplay between occludin and ZO-1 is redox sensitive". doi:10.17169/refubium-12742.{{cite journal}}: Cite journal requires |journal= (help)
  9. 1 2 Castro V, Bertrand L, Luethen M, Dabrowski S, Lombardi J, Morgan L, et al. (March 2016). "Occludin controls HIV transcription in brain pericytes via regulation of SIRT-1 activation". FASEB Journal. 30 (3): 1234–46. doi:10.1096/fj.15-277673. PMC   4750406 . PMID   26601824.
  10. ↑ Bauer H, Stelzhammer W, Fuchs R, Weiger TM, Danninger C, Probst G, Krizbai IA (August 1999). "Astrocytes and neurons express the tight junction-specific protein occludin in vitro". Experimental Cell Research. 250 (2): 434–8. doi:10.1006/excr.1999.4558. PMID   10413597.
  11. ↑ Romanitan MO, Popescu BO, Winblad B, Bajenaru OA, Bogdanovic N (2007). "Occludin is overexpressed in Alzheimer's disease and vascular dementia". Journal of Cellular and Molecular Medicine. 11 (3): 569–79. doi:10.1111/j.1582-4934.2007.00047.x. PMC   3922362 . PMID   17635647.
  12. ↑ Rescigno M, Rotta G, Valzasina B, Ricciardi-Castagnoli P (December 2001). "Dendritic cells shuttle microbes across gut epithelial monolayers". Immunobiology. 204 (5): 572–81. doi:10.1078/0171-2985-00094. PMID   11846220.
  13. ↑ Castro V, Bertrand L, Luethen M, Dabrowski S, Lombardi J, Morgan L, et al. (March 2016). "Occludin controls HIV transcription in brain pericytes via regulation of SIRT-1 activation". FASEB Journal. 30 (3): 1234–46. doi:10.1096/fj.15-277673. PMC   4750406 . PMID   26601824.
  14. ↑ 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. PMID   9824772. S2CID   23713562.
  15. ↑ 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. doi:10.3967/0895-3988.2011.04.016. PMID   22108334.
  16. 1 2 Castro V, Skowronska M, Lombardi J, He J, Seth N, Velichkovska M, Toborek M (February 2018). "Occludin regulates glucose uptake and ATP production in pericytes by influencing AMP-activated protein kinase activity". Journal of Cerebral Blood Flow and Metabolism. 38 (2): 317–332. doi:10.1177/0271678X17720816. PMC   5951017 . PMID   28718701.
  17. ↑ Ando-Akatsuka Y, Saitou M, Hirase T, Kishi M, Sakakibara A, Itoh M, et al. (April 1996). "Interspecies diversity of the occludin sequence: cDNA cloning of human, mouse, dog, and rat-kangaroo homologues". The Journal of Cell Biology. 133 (1): 43–7. doi:10.1083/jcb.133.1.43. PMC   2120780 . PMID   8601611.
  18. ↑ "Entrez Gene: OCLN occludin".
  19. ↑ "OCLN occludin [Homo sapiens (human)] - Gene - NCBI".
  20. ↑ Chen Y, Merzdorf C, Paul DL, Goodenough DA (August 1997). "COOH terminus of occludin is required for tight junction barrier function in early Xenopus embryos". The Journal of Cell Biology. 138 (4): 891–9. doi:10.1083/jcb.138.4.891. PMC   2138038 . PMID   9265654.
  21. 1 2 3 Feldman GJ, Mullin JM, Ryan MP (April 2005). "Occludin: structure, function and regulation". Advanced Drug Delivery Reviews. 57 (6): 883–917. doi:10.1016/j.addr.2005.01.009. PMID   15820558.
  22. ↑ Saito AC, Higashi T, Fukazawa Y, Otani T, Tauchi M, Higashi AY, Furuse M, et al. (April 2021). "Occludin and tricellulin facilitate formation of anastomosing tight-junction strand network to improve barrier function". Molecular Biology of the Cell. 32 (8): 722–38. doi:10.1091/mbc.E20-07-0464. PMC   8108510 . PMID   33566640.
  23. ↑ Saitou M, Furuse M, Sasaki H, Schulzke JD, Fromm M, Takano H, et al. (December 2000). "Complex phenotype of mice lacking occludin, a component of tight junction strands". Molecular Biology of the Cell. 11 (12): 4131–42. doi:10.1091/mbc.11.12.4131. PMC   15062 . PMID   11102513.
  24. ↑ Martin TA, Mansel RE, Jiang WG (November 2010). "Loss of occludin leads to the progression of human breast cancer". International Journal of Molecular Medicine. 26 (5): 723–34. doi: 10.3892/ijmm_00000519 . PMID   20878095.
  25. ↑ Beeman N, Webb PG, Baumgartner HK (February 2012). "Occludin is required for apoptosis when claudin-claudin interactions are disrupted". Cell Death & Disease. 3 (2): e273. doi:10.1038/cddis.2012.14. PMC   3288343 . PMID   22361748.
  26. ↑ Osanai M, Murata M, Nishikiori N, Chiba H, Kojima T, Sawada N (September 2006). "Epigenetic silencing of occludin promotes tumorigenic and metastatic properties of cancer cells via modulations of unique sets of apoptosis-associated genes". Cancer Research. 66 (18): 9125–33. doi: 10.1158/0008-5472.CAN-06-1864 . PMID   16982755.
  27. ↑ Peng BH, Lee JC, Campbell GA (December 2003). "In vitro protein complex formation with cytoskeleton-anchoring domain of occludin identified by limited proteolysis". The Journal of Biological Chemistry. 278 (49): 49644–51. doi: 10.1074/jbc.M302782200 . PMID   14512431. S2CID   33062461.
  28. ↑ Itoh M, Morita K, Tsukita S (February 1999). "Characterization of ZO-2 as a MAGUK family member associated with tight as well as adherens junctions with a binding affinity to occludin and alpha catenin". The Journal of Biological Chemistry. 274 (9): 5981–6. doi: 10.1074/jbc.274.9.5981 . PMID   10026224. S2CID   20269381.
  29. ↑ Wittchen ES, Haskins J, Stevenson BR (December 1999). "Protein interactions at the tight junction. Actin has multiple binding partners, and ZO-1 forms independent complexes with ZO-2 and ZO-3". The Journal of Biological Chemistry. 274 (49): 35179–85. doi: 10.1074/jbc.274.49.35179 . PMID   10575001. S2CID   23928833.
  30. ↑ Chen YH, Lu Q, Goodenough DA, Jeansonne B (April 2002). "Nonreceptor tyrosine kinase c-Yes interacts with occludin during tight junction formation in canine kidney epithelial cells". Molecular Biology of the Cell. 13 (4): 1227–37. doi:10.1091/mbc.01-08-0423. PMC   102264 . PMID   11950934.
  31. ↑ Fanning AS, Jameson BJ, Jesaitis LA, Anderson JM (November 1998). "The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton". The Journal of Biological Chemistry. 273 (45): 29745–53. doi: 10.1074/jbc.273.45.29745 . PMID   9792688. S2CID   23935899.
  32. ↑ Rao RK, Basuroy S, Rao VU, Karnaky KJ, Gupta A (December 2002). "Tyrosine phosphorylation and dissociation of occludin-ZO-1 and E-cadherin-beta-catenin complexes from the cytoskeleton by oxidative stress". The Biochemical Journal. 368 (Pt 2): 471–81. doi:10.1042/BJ20011804. PMC   1222996 . PMID   12169098.

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