Occludin

Occludin is an enzyme (EC 1.6) that oxidizes NADH[5]. It was first identified in epithelial cells as a 65 kDa integral plasma-membrane protein localized at the tight junctions[6], and together with Claudins, and zonula occludens-1 (ZO-1), has been considered a staple of tight junctions. Although it was originally 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 its selective phosphorylation.[7], and its redox-sensitive dimerization[8][9] However, mounting evidence demonstrated that occludin is not only present in epithelial/endothelial cells, but is also found in large amounts in cells that do not have tight junctions but have very active metabolism: pericytes,[10] neurons and astrocytes,[11] oligodendrocytes,[12], dendritic cells,[13] monocytes/macrophages[14] lymphocytes,[15] and myocardium.[16] 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.[17] Furthermore, manipulation of occludin content in human cells is capable of influencing the expression of glucose transporters,[17] and the activation of transcription factors like NFkB, and histones like sirtuins, which in a laboratory setting, proved capable of diminishing HIV replication rates in infected human macrophages.[5]

OCLN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesOCLN, BLCPMG, PPP1R115, occludin, PTORCH1
External IDsOMIM: 602876 MGI: 106183 HomoloGene: 1905 GeneCards: OCLN
Gene location (Human)
Chr.Chromosome 5 (human)[1]
Band5q13.2Start69,492,292 bp[1]
End69,558,104 bp[1]
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

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 MbChr 13: 100.5 – 100.55 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Diagram of Tight junction.

Gene location

In humans is encoded by the OCLN gene[18][19] 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[20]. 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.[21] The C-terminus also interacts with several cytoplasmic proteins of the junctional plaque and interacts with signaling molecules responsible for cell survival.[22] The N-terminus of occludin experimentally has been linked to involvement in tight junction sealing/barrier properties.[22] 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.[22]

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. 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.[31][32]

References
  1. ENSG00000273814 GRCh38: Ensembl release 89: ENSG00000197822, ENSG00000273814 - Ensembl, May 2017
  2. 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. 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.
  6. 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.
  7. 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.
  8. 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.
  9. Villela C, Manuel V (2011). "The interplay between occludin and ZO-1 is redox sensitive". doi:10.17169/refubium-12742.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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. PMID 26601824.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. "Entrez Gene: OCLN occludin".
  20. "OCLN occludin [Homo sapiens (human)] - Gene - NCBI".
  21. 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.
  22. 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.
  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.
  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.
  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.
  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.
  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.

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. doi:10.1083/jcb.127.6.1617. PMC 2120300. 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. PMC 1857944. 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. doi:10.1083/jcb.141.1.199. PMC 2132714. 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. doi:10.1002/(SICI)1097-4652(199911)181:2<319::AID-JCP14>3.0.CO;2-S. PMID 10497311.
  • 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. 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. doi:10.1083/jcb.147.6.1351. PMC 2168087. 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. doi:10.1074/jbc.M001530200. PMID 10749869.
  • 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. doi:10.1093/molehr/7.3.279. 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. doi:10.1074/jbc.M104923200. PMID 11502742.
  • 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. PMID 11679090.
  • 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. 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. doi:10.1046/j.0022-202x.2001.01493.x. 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. doi:10.1074/jbc.M111384200. PMID 11782481.
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