Redox Regulation of Cell Contacts by Tricellulin and Occludin: Redox-Sensitive Cysteine Sites in Tricellulin Regulate Both Tri- and Bicellular Junctions in Tissue Barriers as Shown in Hypoxia and Ischemia

Cording, Jimmi; Günther, Ramona; Vigolo, Emilia; Tscheik, Christian; Winkler, Lars; Schlattner, Isabella; Lorenz, Dorothea; Haseloff, Reiner F.; Schmidt‐Ott, Kai M.; Wolburg, Hartwig; Blasig, Ingolf E.

doi:10.1089/ars.2014.6162

Cited by 28 publications

(44 citation statements)

References 46 publications

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“…The localization of Tric at tTJs is altered in pathologies closely linked to alterations in the redox status of the cell. There is evidence that these alterations are caused by a loss of the highly conserved disulfide bridge in the ECL2, comparable to a mechanism described for Occl …”

Section: Introductionsupporting

confidence: 57%

Trictide, a tricellulin‐derived peptide to overcome cellular barriers

Cording¹,

Arslan²,

Staat³

et al. 2017

Annals of the New York Academy of Sciences

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The majority of tight junction (TJ) proteins restrict the paracellular permeation of solutes via their extracellular loops (ECLs). Tricellulin tightens tricellular TJs (tTJs) and regulates bicellular TJ (bTJ) proteins. We demonstrate that the addition of recombinantly produced extracellular loop 2 (ECL2) of tricellulin opens cellular barriers. The peptidomimetic trictide, a synthetic peptide derived from tricellulin ECL2, increases the passage of ions, as well as of small and larger molecules up to 10 kDa, between 16 and 30 h after application to human epithelial colorectal adenocarcinoma cell line 2. Tricellulin and lipolysis-stimulated lipoprotein receptor relocate from tTJs toward bTJs, while the TJ proteins claudin-1 and occludin redistribute from bTJs to the cytosol. Analyzing the opening of the tricellular sealing tube by the peptidomimetic using super-resolution stimulated-emission depletion microscopy revealed a tricellulin-free area at the tricellular region. Cis-interactions (as measured by fluorescence resonance energy transfer) of tricellulin-tricellulin (tTJs), tricellulin-claudin-1, tricellulin-marvelD3, and occludin-occludin (bTJs) were strongly affected by trictide treatment. Circular dichroism spectroscopy and molecular modeling suggest that trictide adopts a β-sheet structure, resulting in a peculiar interaction surface for its binding to tricellulin. In conclusion, trictide is a novel and promising tool for overcoming cellular barriers at bTJs and tTJs with the potential to transiently improve drug delivery.

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Section: Introductionsupporting

confidence: 57%

Trictide, a tricellulin‐derived peptide to overcome cellular barriers

Cording¹,

Arslan²,

Staat³

et al. 2017

Annals of the New York Academy of Sciences

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“…This includes direct effects on tricellulin downregulation or indirect effects via expression changes of angulins or occludin. For example, it is known that tricellulin localization is sensitive to extracellular Ca 2+ levels and redox conditions, which could be altered during hypoxia or ischemia . Additionally, phosphorylation of tricellulin and occludin may regulate tTJ assembly …”

Section: Discussionmentioning

confidence: 99%

Contribution of the tricellular tight junction to paracellular permeability in leaky and tight epithelia

Krug

2017

Annals of the New York Academy of Sciences

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The tricellular tight junction (tTJ) is a potential weak point of the paracellular barrier. For solving the proportional contribution of the tTJ, ion conductances and macromolecule permeabilities were analyzed in cell lines of different leakiness. MDCK II, Caco-2, and HT-29/B6 cells were subjected to two-path impedance spectroscopy and morphological analyses in order to calculate the contribution of the tTJ to paracellular and total ion conductivity. The contribution to macromolecule permeability was evaluated by tricellulin overexpression or knockdown. Tricellulin-dependent macromolecule passage was comparably regulated in leaky and tight epithelia, but relative and absolute ion permeabilities of the tTJs were different. Assuming a minimal (50 pS) and maximal (146 pS) conductivity per single tTJ, the possible range of contribution of the tTJ to paracellular ion conductance amounted to only 0.3-1.1% in the leaky cell line MDCK II, but 3-25% in the moderately tight cell line Caco-2, and not less than 29% in the tight cell line HT-29/B6. In these cells, this resulted in a contribution to total epithelial conductance of 9-32%. In conclusion, in leaky epithelia the bicellular TJ accounts for nearly the entire paracellular ion conductance, whereas in tight epithelia the low bicellular TJ conductance has large impact on the tTJ.

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“…Recent work indicates that chemoattractants increase microvascular permeability by inducing TNF release from adherent neutrophils when they are in close proximity to endothelial junctions (241). The formation of intercellular junctional gaps involve calcium-dependent phosphorylation of myosin light chain kinase and cytoskeletal contraction (460) and also arise via influences on a redox sensor, tricellulin, that is localized to tight junction elements at three-cell endothelial contacts (158). In addition to granulocytes, CD4 + T lymphocytes are also capable of inducing endothelial barrier disruption and increased permeability, which appears to be related to their participation in neutrophil recruitment (512).…”

Section: Cell Types Involved In Postischemic Inflammationmentioning

confidence: 99%

Ischemia/Reperfusion

Kalogeris

Baines

Krenz

et al. 2016

Comprehensive Physiology

647

565

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Ischemic disorders, such as myocardial infarction, stroke, and peripheral vascular disease, are the most common causes of debilitating disease and death in westernized cultures. The extent of tissue injury relates directly to the extent of blood flow reduction and to the length of the ischemic period, which influence the levels to which cellular ATP and intracellular pH are reduced. By impairing ATPase-dependent ion transport, ischemia causes intracellular and mitochondrial calcium levels to increase (calcium overload). Cell volume regulatory mechanisms are also disrupted by the lack of ATP, which can induce lysis of organelle and plasma membranes. Reperfusion, although required to salvage oxygen-starved tissues, produces paradoxical tissue responses that fuel the production of reactive oxygen species (oxygen paradox), sequestration of proinflammatory immunocytes in ischemic tissues, endoplasmic reticulum stress, and development of postischemic capillary no-reflow, which amplify tissue injury. These pathologic events culminate in opening of mitochondrial permeability transition pores as a common end-effector of ischemia/reperfusion (I/R)-induced cell lysis and death. Emerging concepts include the influence of the intestinal microbiome, fetal programming, epigenetic changes, and microparticles in the pathogenesis of I/R. The overall goal of this review is to describe these and other mechanisms that contribute to I/R injury. Because so many different deleterious events participate in I/R, it is clear that therapeutic approaches will be effective only when multiple pathologic processes are targeted. In addition, the translational significance of I/R research will be enhanced by much wider use of animal models that incorporate the complicating effects of risk factors for cardiovascular disease.

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Redox Regulation of Cell Contacts by Tricellulin and Occludin: Redox-Sensitive Cysteine Sites in Tricellulin Regulate Both Tri- and Bicellular Junctions in Tissue Barriers as Shown in Hypoxia and Ischemia

Cited by 28 publications

References 46 publications

Trictide, a tricellulin‐derived peptide to overcome cellular barriers

Trictide, a tricellulin‐derived peptide to overcome cellular barriers

Contribution of the tricellular tight junction to paracellular permeability in leaky and tight epithelia

Ischemia/Reperfusion

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