Structure and Function of Tight Junctions

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Motility and Adhesion".

Deadline for manuscript submissions: closed (15 November 2023) | Viewed by 13661

Special Issue Editors


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Guest Editor
UCL Institute of Ophthalmology, University College London, Bath Street, London EC1V 9EL, UK
Interests: epithelial and endothelial cell biology; cell-cell junctions and adhesion; cell polarity; age-related and inherited retinal disease; neurodegenerative disease; glaucoma

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Guest Editor
UCL Institute of Ophthalmology, University College London, Bath Street, London EC1V 9EL, UK
Interests: cell-cell and extracellular adhesion signalling crosstalk; eye biology and physiology; novel targets for therapy of inflammatory and fibrotic diseases, and cancer, as well as proliferative and degenerative eye diseases

Special Issue Information

Dear Colleagues,

Tight junctions are essential for epithelial and endothelial barrier formation. They are cell–cell adhesion complexes with a remarkable abundance of components ranging from cell adhesion proteins through scaffolding proteins and cytoskeletal linkers to different types of signaling proteins that regulate junctional properties as well as cell and tissue functions. As diverse as their components are their functions that include the formation of semipermeable paracellular diffusion barriers, regulation of cell polarization and maintenance of cell surface polarity, modulation of cell and tissue mechanics and morphogenesis, and regulation of gene expression, cell proliferation, and differentiation. Consequently, tight junctions and their components have been linked to multiple inherited, acute, and chronic diseases such as cancer, viral infections, and inflammatory and degenerative conditions.

The purpose of this Special Issue on the structure and function of tight junctions is to emphasize and discuss recent findings on how tight junctions assemble and function in different cell types, and their role in tissue development and morphogenetic processes. The goal of this Special Issue is to cover the entire range of tight junction biology and their roles in disease with research papers and reviews.

Prof. Dr. Karl Matter
Prof. Dr. Maria Balda
Guest Editors

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Keywords

  • tissue barriers
  • mechanotransduction
  • cytoskeleton
  • cancer
  • inflammation
  • gene expression
  • adhesion
  • polarization
  • endothelia
  • epithelia

Published Papers (7 papers)

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Research

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17 pages, 3373 KiB  
Article
Epithelial Barrier Dysfunction in Diarrhea-Predominant Irritable Bowel Syndrome (IBS-D) via Downregulation of Claudin-1
by Karem Awad, Christian Barmeyer, Christian Bojarski, Oliver Nagel, In-Fah M. Lee, Michal R. Schweiger, Jörg-Dieter Schulzke and Roland Bücker
Cells 2023, 12(24), 2846; https://doi.org/10.3390/cells12242846 - 15 Dec 2023
Cited by 1 | Viewed by 1210
Abstract
Background: In patients with diarrhea-predominant irritable bowel syndrome (IBS-D), the diarrheal mechanisms are largely unknown, and they were examined in this study on colon biopsies. Methods: Electrophysiological measurements were used for monitoring functional changes in the diarrheic colon specimens. In parallel, tight junction [...] Read more.
Background: In patients with diarrhea-predominant irritable bowel syndrome (IBS-D), the diarrheal mechanisms are largely unknown, and they were examined in this study on colon biopsies. Methods: Electrophysiological measurements were used for monitoring functional changes in the diarrheic colon specimens. In parallel, tight junction protein expression was analyzed by Western blot and confocal laser-scanning microscopy, and signaling pathway analysis was performed using RNA sequencing and bioinformatics. Results: Epithelial resistance was decreased, indicating an epithelial leak flux diarrheal mechanism with a molecular correlate of decreased claudin-1 expression, while induction of active anion secretion and impairment of active sodium absorption via the epithelial sodium channel, ENaC, were not detected. The pathway analysis revealed activation of barrier-affecting cytokines TNF-α, IFN-γ, IL-1β and IL-4. Conclusions: Barrier dysfunction as a result of epithelial tight junction changes plays a role in IBS-D as a pathomechanism inducing a leak flux type of diarrhea. Full article
(This article belongs to the Special Issue Structure and Function of Tight Junctions)
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15 pages, 4330 KiB  
Article
Knock Out of CGN and CGNL1 in MDCK Cells Affects Claudin-2 but Has a Minor Impact on Tight Junction Barrier Function
by Marine Maupérin, Ali Sassi, Isabelle Méan, Eric Feraille and Sandra Citi
Cells 2023, 12(15), 2004; https://doi.org/10.3390/cells12152004 - 05 Aug 2023
Viewed by 1684
Abstract
Cingulin (CGN) and paracingulin (CGNL1) are cytoplasmic proteins of tight junctions (TJs), where they play a role in tethering ZO-1 to the actomyosin and microtubule cytoskeletons. The role of CGN and CGNL1 in the barrier function of epithelia is not completely understood. Here, [...] Read more.
Cingulin (CGN) and paracingulin (CGNL1) are cytoplasmic proteins of tight junctions (TJs), where they play a role in tethering ZO-1 to the actomyosin and microtubule cytoskeletons. The role of CGN and CGNL1 in the barrier function of epithelia is not completely understood. Here, we analyzed the effect of the knock out (KO) of either CGN or CGNL1 or both on the paracellular permeability of monolayers of kidney epithelial (MDCK) cells. KO cells displayed a modest but significant increase in the transepithelial resistance (TER) of monolayers both in the steady state and during junction assembly by the calcium switch, whereas the permeability of the monolayers to 3 kDa dextran was not affected. The permeability to sodium was slightly but significantly decreased in KO cells. This phenotype correlated with slightly increased mRNA levels of claudin-2, slightly decreased protein levels of claudin-2, and reduced junctional accumulation of claudin-2, which was rescued by CGN or CGNL1 but not by ZO-1 overexpression. These results confirm previous observations indicating that CGN and CGNL1 are dispensable for the barrier function of epithelia and suggest that the increase in the TER in clonal lines of MDCK cells KO for CGN, CGNL1, or both is due to reduced protein expression and junctional accumulation of the sodium pore-forming claudin, claudin-2. Full article
(This article belongs to the Special Issue Structure and Function of Tight Junctions)
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13 pages, 4114 KiB  
Article
The Src-Family Kinases SRC and BLK Contribute to the CLDN6-Adhesion Signaling
by Naoki Ichikawa-Tomikawa, Kotaro Sugimoto, Korehito Kashiwagi and Hideki Chiba
Cells 2023, 12(13), 1696; https://doi.org/10.3390/cells12131696 - 23 Jun 2023
Viewed by 1028
Abstract
Cell adhesion molecules, including integrins, cadherins, and claudins (CLDNs), are known to activate Src-family kinases (SFKs) that organize a variety of physiological and pathological processes; however, the underlying molecular basis remains unclear. Here, we identify the SFK members that are coupled with the [...] Read more.
Cell adhesion molecules, including integrins, cadherins, and claudins (CLDNs), are known to activate Src-family kinases (SFKs) that organize a variety of physiological and pathological processes; however, the underlying molecular basis remains unclear. Here, we identify the SFK members that are coupled with the CLDN6-adhesion signaling. Among SFK subtypes, BLK, FGR, HCK, and SRC were highly expressed in F9 cells and concentrated with CLDN6 along cell borders during epithelial differentiation. Immunoprecipitation assay showed that BLK and SRC, but not FGR or HCK, form a complex with CLDN6 via the C-terminal cytoplasmic domain. We also demonstrated, by pull-down assay, that recombinant BLK and SRC proteins directly bind to the C-terminal cytoplasmic domain of CLDN6 (CLDN6C). Unexpectedly, both recombinant SFK proteins recognized the CLDN6C peptide in a phosphotyrosine-independent manner. Furthermore, by comparing phenotypes of F9:Cldn6:Blk−/− and F9:Cldn6:Src−/− cells with those of wild-type F9 and F9:Cldn6 cells, we revealed that BLK and SRC are essential for CLDN6-triggered cellular events, namely epithelial differentiation and the expression of retinoid acid receptor target genes. These results indicate that selective SFK members appear to participate in the CLDN-adhesion signaling. Full article
(This article belongs to the Special Issue Structure and Function of Tight Junctions)
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17 pages, 2380 KiB  
Article
Impaired Intestinal Permeability of Tricellular Tight Junctions in Patients with Irritable Bowel Syndrome with Mixed Bowel Habits (IBS-M)
by Karem Awad, Christian Barmeyer, Christian Bojarski, Oliver Nagel, In-Fah M. Lee, Michal R. Schweiger, Jörg-Dieter Schulzke and Roland Bücker
Cells 2023, 12(2), 236; https://doi.org/10.3390/cells12020236 - 05 Jan 2023
Cited by 11 | Viewed by 1966
Abstract
Background: The underlying pathophysiology of irritable bowel syndrome (IBS) is still unclear. Our aim was to investigate the pathophysiological mechanisms of diarrhea, constipation, and antigen uptake in mixed-type IBS (IBS-M). Methods: Colonoscopic biopsies were obtained from IBS-M patients. Epithelial transport and barrier function [...] Read more.
Background: The underlying pathophysiology of irritable bowel syndrome (IBS) is still unclear. Our aim was to investigate the pathophysiological mechanisms of diarrhea, constipation, and antigen uptake in mixed-type IBS (IBS-M). Methods: Colonoscopic biopsies were obtained from IBS-M patients. Epithelial transport and barrier function of colonic mucosae were characterized in Ussing chambers using impedance spectroscopy. Mucosal permeability to macromolecules was measured. Western blotting for tight junction (TJ) proteins was performed and their subcellular localization was visualized by confocal microscopy. RNA-sequencing was performed for gene expression and signaling pathway analysis. Results: In IBS-M, epithelial resistance and ENaC-dependent sodium absorption were unchanged, while short-circuit current reflecting chloride secretion was reduced. Concomitantly, epithelial permeability for fluorescein and FITC-dextran-4000 increased. TJ protein expression of occludin decreased, whereas claudins were unaltered. Confocal microscopy revealed the de-localization of tricellulin from tricellular TJs. Involved pathways were detected as proinflammatory cytokine pathways, LPS, PGE2, NGF, and vitamin D. Conclusions: Decreased anion secretion explains constipation in IBS-M, while ion permeability and sodium absorption were unaltered. Reduced occludin expression resulted in the delocalization of tricellulin from the tricellular TJ, leading to increased macromolecular permeability that contributes to antigen influx into the mucosa and perpetuates a low-grade inflammatory process. Full article
(This article belongs to the Special Issue Structure and Function of Tight Junctions)
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30 pages, 14753 KiB  
Article
ZO-1 Guides Tight Junction Assembly and Epithelial Morphogenesis via Cytoskeletal Tension-Dependent and -Independent Functions
by Alexis J. Haas, Ceniz Zihni, Susanne M. Krug, Riccardo Maraspini, Tetsuhisa Otani, Mikio Furuse, Alf Honigmann, Maria S. Balda and Karl Matter
Cells 2022, 11(23), 3775; https://doi.org/10.3390/cells11233775 - 25 Nov 2022
Cited by 8 | Viewed by 4551
Abstract
Formation and maintenance of tissue barriers require the coordination of cell mechanics and cell–cell junction assembly. Here, we combined methods to modulate ECM stiffness and to measure mechanical forces on adhesion complexes to investigate how tight junctions regulate cell mechanics and epithelial morphogenesis. [...] Read more.
Formation and maintenance of tissue barriers require the coordination of cell mechanics and cell–cell junction assembly. Here, we combined methods to modulate ECM stiffness and to measure mechanical forces on adhesion complexes to investigate how tight junctions regulate cell mechanics and epithelial morphogenesis. We found that depletion of the tight junction adaptor ZO-1 disrupted junction assembly and morphogenesis in an ECM stiffness-dependent manner and led to a stiffness-dependant reorganisation of active myosin. Both junction formation and morphogenesis were rescued by inhibition of actomyosin contractility. ZO-1 depletion also impacted mechanical tension at cell-matrix and E-cadherin-based cell–cell adhesions. The effect on E-cadherin also depended on ECM stiffness and correlated with effects of ECM stiffness on actin cytoskeleton organisation. However, ZO-1 knockout also revealed tension-independent functions of ZO-1. ZO-1-deficient cells could assemble functional barriers at low tension, but their tight junctions remained corrupted with strongly reduced and discontinuous recruitment of junctional components. Our results thus reveal that reciprocal regulation between ZO-1 and cell mechanics controls tight junction assembly and epithelial morphogenesis, and that, in a second, tension-independent step, ZO-1 is required to assemble morphologically and structurally fully assembled and functionally normal tight junctions. Full article
(This article belongs to the Special Issue Structure and Function of Tight Junctions)
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Review

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32 pages, 1768 KiB  
Review
Regulation of Epithelial and Endothelial Barriers by Molecular Chaperones
by Susana Lechuga, Armando Marino-Melendez, Nayden G. Naydenov, Atif Zafar, Manuel B. Braga-Neto and Andrei I. Ivanov
Cells 2024, 13(5), 370; https://doi.org/10.3390/cells13050370 - 21 Feb 2024
Viewed by 843
Abstract
The integrity and permeability of epithelial and endothelial barriers depend on the formation of tight junctions, adherens junctions, and a junction-associated cytoskeleton. The establishment of this junction–cytoskeletal module relies on the correct folding and oligomerization of its protein components. Molecular chaperones are known [...] Read more.
The integrity and permeability of epithelial and endothelial barriers depend on the formation of tight junctions, adherens junctions, and a junction-associated cytoskeleton. The establishment of this junction–cytoskeletal module relies on the correct folding and oligomerization of its protein components. Molecular chaperones are known regulators of protein folding and complex formation in different cellular compartments. Mammalian cells possess an elaborate chaperone network consisting of several hundred chaperones and co-chaperones. Only a small part of this network has been linked, however, to the regulation of intercellular adhesions, and the systematic analysis of chaperone functions at epithelial and endothelial barriers is lacking. This review describes the functions and mechanisms of the chaperone-assisted regulation of intercellular junctions. The major focus of this review is on heat shock protein chaperones, their co-chaperones, and chaperonins since these molecules are the focus of the majority of the articles published on the chaperone-mediated control of tissue barriers. This review discusses the roles of chaperones in the regulation of the steady-state integrity of epithelial and vascular barriers as well as the disruption of these barriers by pathogenic factors and extracellular stressors. Since cytoskeletal coupling is essential for junctional integrity and remodeling, chaperone-assisted assembly of the actomyosin cytoskeleton is also discussed. Full article
(This article belongs to the Special Issue Structure and Function of Tight Junctions)
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13 pages, 991 KiB  
Review
Cell Adhesion at the Tight Junctions: New Aspects and New Functions
by Nicolina Wibbe and Klaus Ebnet
Cells 2023, 12(23), 2701; https://doi.org/10.3390/cells12232701 - 24 Nov 2023
Cited by 2 | Viewed by 1265
Abstract
Tight junctions (TJ) are cell–cell adhesive structures that define the permeability of barrier-forming epithelia and endothelia. In contrast to this seemingly static function, TJs display a surprisingly high molecular complexity and unexpected dynamic regulation, which allows the TJs to maintain a barrier in [...] Read more.
Tight junctions (TJ) are cell–cell adhesive structures that define the permeability of barrier-forming epithelia and endothelia. In contrast to this seemingly static function, TJs display a surprisingly high molecular complexity and unexpected dynamic regulation, which allows the TJs to maintain a barrier in the presence of physiological forces and in response to perturbations. Cell–cell adhesion receptors play key roles during the dynamic regulation of TJs. They connect individual cells within cellular sheets and link sites of cell–cell contacts to the underlying actin cytoskeleton. Recent findings support the roles of adhesion receptors in transmitting mechanical forces and promoting phase separation. In this review, we discuss the newly discovered functions of cell adhesion receptors localized at the TJs and their role in the regulation of the barrier function. Full article
(This article belongs to the Special Issue Structure and Function of Tight Junctions)
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