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Claudins and Other Tight Junction Proteins

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Abstract

Epithelial transport relies on the proper function and regulation of the tight junction (TJ), other‐wise uncontrolled paracellular leakage of solutes and water would occur. They also act as a fence against mixing of membrane proteins of the apical and basolateral side. The proteins determining paracellular transport consist of four transmembrane regions, intracellular N and C terminals, one intracellular and two extracellular loops (ECLs). The ECLs interact laterally and with counterparts of the neighboring cell and by this achieve a general sealing function. Two TJ protein families can be distinguished, claudins, comprising 27 members in mammals, and TJ‐associated MARVEL proteins (TAMP), comprising occludin, tricellulin, and MarvelD3. They are linked to a multitude of TJ‐associated regulatory and scaffolding proteins. The major TJ proteins are classified according to the physiological role they play in enabling or preventing paracellular transport. Many TJ proteins have sealing functions (claudins 1, 3, 5, 11, 14, 19, and tricellulin). In contrast, a significant number of claudins form channels across TJs which feature selectivity for cations (claudins 2, 10b, and 15), anions (claudin‐10a and ‐17), or are permeable to water (claudin‐2). For several TJ proteins, function is yet unclear as their effects on epithelial barriers are inconsistent (claudins 4, 7, 8, 16, and occludin). TJs undergo physiological and pathophysiological regulation by altering protein composition or abundance. Major pathophysiological conditions which involve changes in TJ protein composition are (1) effects of pathogens binding to TJ proteins, (2) altered TJ protein composition during inflammation and infection, and (3) altered TJ protein expression in cancers. © 2012 American Physiological Society. Compr Physiol 2:1819‐1852, 2012.

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Figure 1. Figure 1.

Features of bicellular and tricellular tight junctions. (A) Freeze fracture electron micrograph of a bicellular (bTJ) and a tricellular (tTJ) TJ of the colon carcinoma cell line HT‐29/B6. MV, microvilli (S.M. Krug, unpublished). (B) Confocal laser scanning micrograph (xy scan) of occludin (red) marking the bTJ, and tricellulin (green; yellow in merged image) marking the tTJ of the colon carcinoma cell line Caco‐2 (S.M. Krug, unpublished). (C) Confocal laser scanning micrograph (xz scan) of the canine kidney cell line MDCK II. 10 kDa (green) and 4 kDa (red) dextran was added to the basolateral side of the cell layer. Diffusion of 10 kDa dextran along the paracellular space is stopped at the TJ (barrier function of the TJ). In contrast, 4 kDa dextran is able to pass the TJ and to enter the apical space (channel function of the TJ). Together, these two features mark the gate function of the epithelial cell layer. (D) Confocal laser scanning micrograph (xy and xz scan) of an HT‐29/B6 cell layer in the absence (left) and presence (right) of the Ca2+ chelator EGTA. In the intact layer, E‐cadherin (green) is confined to the (baso)lateral membrane by the TJ (red, claudin‐5) visualizing the fence function of the TJ. Reduction of the extracellular Ca2+ concentration causes internalization of the TJ proteins and diffusion of E‐cadherin into the apical membrane compartment (J.F. Richter, unpublished).

Figure 2. Figure 2.

Features of bicellular and tricellular tight junctions. (A) Freeze fracture electron micrograph of a bicellular (bTJ) and a tricellular (tTJ) TJ of the colon carcinoma cell line HT‐29/B6. MV, microvilli (S.M. Krug, unpublished). (B) Confocal laser scanning micrograph (xy scan) of occludin (red) marking the bTJ, and tricellulin (green; yellow in merged image) marking the tTJ of the colon carcinoma cell line Caco‐2 (S.M. Krug, unpublished). (C) Confocal laser scanning micrograph (xz scan) of the canine kidney cell line MDCK II. 10 kDa (green) and 4 kDa (red) dextran was added to the basolateral side of the cell layer. Diffusion of 10 kDa dextran along the paracellular space is stopped at the TJ (barrier function of the TJ). In contrast, 4 kDa dextran is able to pass the TJ and to enter the apical space (channel function of the TJ). Together, these two features mark the gate function of the epithelial cell layer. (D) Confocal laser scanning micrograph (xy and xz scan) of an HT‐29/B6 cell layer in the absence (left) and presence (right) of the Ca2+ chelator EGTA. In the intact layer, E‐cadherin (green) is confined to the (baso)lateral membrane by the TJ (red, claudin‐5) visualizing the fence function of the TJ. Reduction of the extracellular Ca2+ concentration causes internalization of the TJ proteins and diffusion of E‐cadherin into the apical membrane compartment (J.F. Richter, unpublished).

Figure 3. Figure 3.

Tight junctions and associated proteins. Integral membrane proteins of the TJ are binding to numerous intracellular TJ‐associated proteins that serve scaffolding and regulatory functions.

Figure 4. Figure 4.

Phylogenetic classification of claudins. (A) Classification according to references , , , , , , , . (B) Classification according to Loh et al. (reference ). (C) Phylogenetic tree introduced by the present review.

Figure 5. Figure 5.

Phylogenetic classification of claudins. (A) Classification according to references , , , , , , , . (B) Classification according to Loh et al. (reference ). (C) Phylogenetic tree introduced by the present review.

Figure 6. Figure 6.

Phylogenetic classification of claudins. (A) Classification according to references , , , , , , , . (B) Classification according to Loh et al. (reference ). (C) Phylogenetic tree introduced by the present review.

Figure 7. Figure 7.

Phylogenetic classification of the tight junction‐associated MARVEL proteins (TAMP) family (red) as part of the MARVEL‐domain superfamily. Used and modified with kind permission of Mary Ann Liebert, Inc., from Antioxidants & Redox Signaling 15: 1196, Figure , Blasig et al. 2011, Occludin protein family: oxidative stress and reducing conditions.

Figure 8. Figure 8.

Effect of tricellulin overexpression on permeability to paracellular tracers of various sizes. Tricellulin was overexpressed to various degrees in MDCK II cells. Week overexpression (blue) resulted in purely tricellular localization while strong overexpression (red) resulted in tricellular and bicellular localization of tricellulin. Vector‐transfected control cells (black) showed very weak, tricellular localization of endogenous tricellulin. Purely tricellular distribution caused a sealing of the paracellular space against larger solutes (diameter > 10 Å, cf. blue shaded area). In contrast, bicellular distribution caused additional sealing against small solutes (diameter < 10 Å, cf. red shaded area). (Based on data by reference .)

Figure 9. Figure 9.

Eisenman sequences for monovalent cations as determined by dilution potential measurements (based on data from references and ). MDCK C7 cells were transfected either with claudin‐2, claudin‐10a, claudin‐10b, or the empty vector (control). Under control conditions and when transfected with claudin‐10a (not shown) permeability sequence followed Eisenman sequence IV (i.e., highest permeability to K+, least permeability to Li+). When transfected with claudin‐2 or ‐10b, cation permeability increased greatly and permeability sequences changed to Eisenman sequence IX and X, respectively (highest permeability to Na+, least permeability to Cs+), indicating an almost complete removal of the ion's hydration shell within the pore. Coculture of cells expressing claudin‐10a and ‐10b also caused an increase in cation permeability; however, this was associated with a complete loss of selectivity, as indicated by a reversal of the permeability sequence to Eisenman sequence I (highest permeability to Cs+, least permeability to Li+).

Figure 10. Figure 10.

ECL1 amino acid sequence of channel‐forming claudins. δ, charge found to be important for ion selectivity in mutation approach; /, charge found not to be important for ion selectivity in mutation approach; ?, potentially important for ion selectivity, but not yet investigated (based on data by references , and ).

Figure 11. Figure 11.

Claudin‐claudin interactions. (A, B) Model of two claudin‐5 ECL2 interacting in trans by hydrophobic interaction of amino acids F147, Y148, and Y158 (viewed from two different angles). Used with kind permission of FASEB, from Formation of tight junction: determinants of homophilic interaction between classic claudins. FASEB J 22: 155, Figure 7D and E; permission conveyed through Copyright Clearance Center, Inc. (C) Model of cis and trans interactions between the claudins 1, 2, 3, 5, and 12 and working hypothesis for TJ assembly. Step 1 and 2, cis homo‐ and hetero‐oligomers (dimers to hexamers, i.e., n = 2‐6) are formed in the endoplasmic reticulum (ER) and/or Golgi apparatus. Documented hetero‐cis‐interactions comprise claudin‐1/‐5, claudin‐2/‐5, claudin‐3/‐5, and claudin‐1/‐3, but not claudin‐2/‐3. Claudin‐12 was not observed to interact with any of of the other claudins investigated. Step 3, insertion of cis‐oligomers into the plasma membrane. Steps 4 and 5, trans‐interactions initiate TJ strand formation. As claudin‐12 neither interacted with claudins‐1, 2, 3, or 5, nor with ZO‐1 due to its lack of a PDZ binding motif, interaction with a yet unidentified claudin‐X is postulated that recruits claudin‐12 into the TJ. Used with kind permission from Springer Science+Business Media B.V., from Cell Mol Life Sci 2011 DOI: 10.1007/s00018‐011‐0680‐z, Elucidating the principles of the molecular organization of heteropolymeric tight junction strands.

Figure 10a, © Springer Basel AG.
Figure 12. Figure 12.

Claudin‐claudin interactions. (A, B) Model of two claudin‐5 ECL2 interacting in trans by hydrophobic interaction of amino acids F147, Y148, and Y158 (viewed from two different angles). Used with kind permission of FASEB, from Formation of tight junction: determinants of homophilic interaction between classic claudins. FASEB J 22: 155, Figure 7D and E; permission conveyed through Copyright Clearance Center, Inc. (C) Model of cis and trans interactions between the claudins 1, 2, 3, 5, and 12 and working hypothesis for TJ assembly. Step 1 and 2, cis homo‐ and hetero‐oligomers (dimers to hexamers, i.e., n = 2‐6) are formed in the endoplasmic reticulum (ER) and/or Golgi apparatus. Documented hetero‐cis‐interactions comprise claudin‐1/‐5, claudin‐2/‐5, claudin‐3/‐5, and claudin‐1/‐3, but not claudin‐2/‐3. Claudin‐12 was not observed to interact with any of of the other claudins investigated. Step 3, insertion of cis‐oligomers into the plasma membrane. Steps 4 and 5, trans‐interactions initiate TJ strand formation. As claudin‐12 neither interacted with claudins‐1, 2, 3, or 5, nor with ZO‐1 due to its lack of a PDZ binding motif, interaction with a yet unidentified claudin‐X is postulated that recruits claudin‐12 into the TJ. Used with kind permission from Springer Science+Business Media B.V., from Cell Mol Life Sci 2011 DOI: 10.1007/s00018‐011‐0680‐z, Elucidating the principles of the molecular organization of heteropolymeric tight junction strands.

Figure 10a, © Springer Basel AG.
Figure 13. Figure 13.

Claudin‐3 ECL2 interaction with CPE. (A) Helix‐turn‐helix model of claudin‐3 ECL2. (B) Model of the interaction between claudin‐3 ECL2 and a binding pocket within the C‐terminus of Clostridium perfringens enterotoxin (CPE), formed by amino acid Y306, Y310, and Y312. Used with kind permission of MDPI, Basel, Switzerland from Toxins 2, 1350, Figure , doi:10.3390/toxins20613362010 (). On the interaction of Clostridium perfringens enterotoxin with claudins.



Figure 1.

Features of bicellular and tricellular tight junctions. (A) Freeze fracture electron micrograph of a bicellular (bTJ) and a tricellular (tTJ) TJ of the colon carcinoma cell line HT‐29/B6. MV, microvilli (S.M. Krug, unpublished). (B) Confocal laser scanning micrograph (xy scan) of occludin (red) marking the bTJ, and tricellulin (green; yellow in merged image) marking the tTJ of the colon carcinoma cell line Caco‐2 (S.M. Krug, unpublished). (C) Confocal laser scanning micrograph (xz scan) of the canine kidney cell line MDCK II. 10 kDa (green) and 4 kDa (red) dextran was added to the basolateral side of the cell layer. Diffusion of 10 kDa dextran along the paracellular space is stopped at the TJ (barrier function of the TJ). In contrast, 4 kDa dextran is able to pass the TJ and to enter the apical space (channel function of the TJ). Together, these two features mark the gate function of the epithelial cell layer. (D) Confocal laser scanning micrograph (xy and xz scan) of an HT‐29/B6 cell layer in the absence (left) and presence (right) of the Ca2+ chelator EGTA. In the intact layer, E‐cadherin (green) is confined to the (baso)lateral membrane by the TJ (red, claudin‐5) visualizing the fence function of the TJ. Reduction of the extracellular Ca2+ concentration causes internalization of the TJ proteins and diffusion of E‐cadherin into the apical membrane compartment (J.F. Richter, unpublished).



Figure 2.

Features of bicellular and tricellular tight junctions. (A) Freeze fracture electron micrograph of a bicellular (bTJ) and a tricellular (tTJ) TJ of the colon carcinoma cell line HT‐29/B6. MV, microvilli (S.M. Krug, unpublished). (B) Confocal laser scanning micrograph (xy scan) of occludin (red) marking the bTJ, and tricellulin (green; yellow in merged image) marking the tTJ of the colon carcinoma cell line Caco‐2 (S.M. Krug, unpublished). (C) Confocal laser scanning micrograph (xz scan) of the canine kidney cell line MDCK II. 10 kDa (green) and 4 kDa (red) dextran was added to the basolateral side of the cell layer. Diffusion of 10 kDa dextran along the paracellular space is stopped at the TJ (barrier function of the TJ). In contrast, 4 kDa dextran is able to pass the TJ and to enter the apical space (channel function of the TJ). Together, these two features mark the gate function of the epithelial cell layer. (D) Confocal laser scanning micrograph (xy and xz scan) of an HT‐29/B6 cell layer in the absence (left) and presence (right) of the Ca2+ chelator EGTA. In the intact layer, E‐cadherin (green) is confined to the (baso)lateral membrane by the TJ (red, claudin‐5) visualizing the fence function of the TJ. Reduction of the extracellular Ca2+ concentration causes internalization of the TJ proteins and diffusion of E‐cadherin into the apical membrane compartment (J.F. Richter, unpublished).



Figure 3.

Tight junctions and associated proteins. Integral membrane proteins of the TJ are binding to numerous intracellular TJ‐associated proteins that serve scaffolding and regulatory functions.



Figure 4.

Phylogenetic classification of claudins. (A) Classification according to references , , , , , , , . (B) Classification according to Loh et al. (reference ). (C) Phylogenetic tree introduced by the present review.



Figure 5.

Phylogenetic classification of claudins. (A) Classification according to references , , , , , , , . (B) Classification according to Loh et al. (reference ). (C) Phylogenetic tree introduced by the present review.



Figure 6.

Phylogenetic classification of claudins. (A) Classification according to references , , , , , , , . (B) Classification according to Loh et al. (reference ). (C) Phylogenetic tree introduced by the present review.



Figure 7.

Phylogenetic classification of the tight junction‐associated MARVEL proteins (TAMP) family (red) as part of the MARVEL‐domain superfamily. Used and modified with kind permission of Mary Ann Liebert, Inc., from Antioxidants & Redox Signaling 15: 1196, Figure , Blasig et al. 2011, Occludin protein family: oxidative stress and reducing conditions.



Figure 8.

Effect of tricellulin overexpression on permeability to paracellular tracers of various sizes. Tricellulin was overexpressed to various degrees in MDCK II cells. Week overexpression (blue) resulted in purely tricellular localization while strong overexpression (red) resulted in tricellular and bicellular localization of tricellulin. Vector‐transfected control cells (black) showed very weak, tricellular localization of endogenous tricellulin. Purely tricellular distribution caused a sealing of the paracellular space against larger solutes (diameter > 10 Å, cf. blue shaded area). In contrast, bicellular distribution caused additional sealing against small solutes (diameter < 10 Å, cf. red shaded area). (Based on data by reference .)



Figure 9.

Eisenman sequences for monovalent cations as determined by dilution potential measurements (based on data from references and ). MDCK C7 cells were transfected either with claudin‐2, claudin‐10a, claudin‐10b, or the empty vector (control). Under control conditions and when transfected with claudin‐10a (not shown) permeability sequence followed Eisenman sequence IV (i.e., highest permeability to K+, least permeability to Li+). When transfected with claudin‐2 or ‐10b, cation permeability increased greatly and permeability sequences changed to Eisenman sequence IX and X, respectively (highest permeability to Na+, least permeability to Cs+), indicating an almost complete removal of the ion's hydration shell within the pore. Coculture of cells expressing claudin‐10a and ‐10b also caused an increase in cation permeability; however, this was associated with a complete loss of selectivity, as indicated by a reversal of the permeability sequence to Eisenman sequence I (highest permeability to Cs+, least permeability to Li+).



Figure 10.

ECL1 amino acid sequence of channel‐forming claudins. δ, charge found to be important for ion selectivity in mutation approach; /, charge found not to be important for ion selectivity in mutation approach; ?, potentially important for ion selectivity, but not yet investigated (based on data by references , and ).



Figure 11.

Claudin‐claudin interactions. (A, B) Model of two claudin‐5 ECL2 interacting in trans by hydrophobic interaction of amino acids F147, Y148, and Y158 (viewed from two different angles). Used with kind permission of FASEB, from Formation of tight junction: determinants of homophilic interaction between classic claudins. FASEB J 22: 155, Figure 7D and E; permission conveyed through Copyright Clearance Center, Inc. (C) Model of cis and trans interactions between the claudins 1, 2, 3, 5, and 12 and working hypothesis for TJ assembly. Step 1 and 2, cis homo‐ and hetero‐oligomers (dimers to hexamers, i.e., n = 2‐6) are formed in the endoplasmic reticulum (ER) and/or Golgi apparatus. Documented hetero‐cis‐interactions comprise claudin‐1/‐5, claudin‐2/‐5, claudin‐3/‐5, and claudin‐1/‐3, but not claudin‐2/‐3. Claudin‐12 was not observed to interact with any of of the other claudins investigated. Step 3, insertion of cis‐oligomers into the plasma membrane. Steps 4 and 5, trans‐interactions initiate TJ strand formation. As claudin‐12 neither interacted with claudins‐1, 2, 3, or 5, nor with ZO‐1 due to its lack of a PDZ binding motif, interaction with a yet unidentified claudin‐X is postulated that recruits claudin‐12 into the TJ. Used with kind permission from Springer Science+Business Media B.V., from Cell Mol Life Sci 2011 DOI: 10.1007/s00018‐011‐0680‐z, Elucidating the principles of the molecular organization of heteropolymeric tight junction strands.

Figure 10a, © Springer Basel AG.


Figure 12.

Claudin‐claudin interactions. (A, B) Model of two claudin‐5 ECL2 interacting in trans by hydrophobic interaction of amino acids F147, Y148, and Y158 (viewed from two different angles). Used with kind permission of FASEB, from Formation of tight junction: determinants of homophilic interaction between classic claudins. FASEB J 22: 155, Figure 7D and E; permission conveyed through Copyright Clearance Center, Inc. (C) Model of cis and trans interactions between the claudins 1, 2, 3, 5, and 12 and working hypothesis for TJ assembly. Step 1 and 2, cis homo‐ and hetero‐oligomers (dimers to hexamers, i.e., n = 2‐6) are formed in the endoplasmic reticulum (ER) and/or Golgi apparatus. Documented hetero‐cis‐interactions comprise claudin‐1/‐5, claudin‐2/‐5, claudin‐3/‐5, and claudin‐1/‐3, but not claudin‐2/‐3. Claudin‐12 was not observed to interact with any of of the other claudins investigated. Step 3, insertion of cis‐oligomers into the plasma membrane. Steps 4 and 5, trans‐interactions initiate TJ strand formation. As claudin‐12 neither interacted with claudins‐1, 2, 3, or 5, nor with ZO‐1 due to its lack of a PDZ binding motif, interaction with a yet unidentified claudin‐X is postulated that recruits claudin‐12 into the TJ. Used with kind permission from Springer Science+Business Media B.V., from Cell Mol Life Sci 2011 DOI: 10.1007/s00018‐011‐0680‐z, Elucidating the principles of the molecular organization of heteropolymeric tight junction strands.

Figure 10a, © Springer Basel AG.


Figure 13.

Claudin‐3 ECL2 interaction with CPE. (A) Helix‐turn‐helix model of claudin‐3 ECL2. (B) Model of the interaction between claudin‐3 ECL2 and a binding pocket within the C‐terminus of Clostridium perfringens enterotoxin (CPE), formed by amino acid Y306, Y310, and Y312. Used with kind permission of MDPI, Basel, Switzerland from Toxins 2, 1350, Figure , doi:10.3390/toxins20613362010 (). On the interaction of Clostridium perfringens enterotoxin with claudins.

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 289. Zheng A, Yuan F, Li Y, Zhu F, Hou P, Li J, Song X, Ding M, Deng H. Claudin‐6 and claudin‐9 function as additional coreceptors for hepatitis C virus. J Virol 81: 12465‐12471, 2007.
 290. Zheng J, Xie Y, Campbell R, Song J, Massachi S, Razi M, Chiu R, Berenson J, Yang OO, Chen IS, Pang S. Involvement of claudin‐7 in HIV infection of CD4(‐) cells. Retrovirology 2: 79, 2005.
 291. Zorko MS, Veranic P, Leskovec NK, Pavlović MD, Lunder T. Expression of tight‐junction proteins in the inflamed and clinically uninvolved skin in patients with venous leg ulcers. Clin Exp Dermatol 34: e949‐e952, 2009.
Further Reading
 1. Günzel D, Krug SM, Rosenthal R, Fromm M. Biophysical methods to study tight junction permeability. Curr Top Membr 65: 39‐78, 2010.
 2. Turksen K (ed). Claudins: Methods and protocols. Methods in Molecular Biology 762: 1‐461, 2011.
 3. Fromm M, Schulzke JD (eds). Molecular structure and function of the tight junction. Ann NY Acad Sci 1165: 1‐346, 2009. (A follow‐up volume will be published by the Ann NY Acad Sci in 2012.)
 4. Yu AS (ed). Claudins. Curr Top Membr 65: 1‐341, 2010.

Futher Reading

Methods in tight junction research:

Günzel D, Krug SM, Rosenthal R, Fromm M. Biophysical methods to study tight junction permeability. Curr Top Membr 65: 39-78, 2010.

Turksen K (ed). Claudins: Methods and protocols. Methods in Molecular Biology 762: pp 1-461, 2011.

Overview of the field:

Fromm M, Schulzke JD (eds). Molecular structure and function of the tight junction. Ann NY Acad Sci 1165: pp 1-346, 2009. (A follow-up volume will be published by the Ann NY Acad Sci in 2012)

Yu AS (ed). Claudins. Current Topics in Membranes 65: pp 1-341, 2010.

 


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How to Cite

Dorothee Günzel, Michael Fromm. Claudins and Other Tight Junction Proteins. Compr Physiol 2012, 2: 1819-1852. doi: 10.1002/cphy.c110045