Non-canonical functions of claudin proteins: Beyond the regulation of cell-cell adhesions

Hagen, Susan J.

doi:10.1080/21688370.2017.1327839

Cited by 78 publications

(79 citation statements)

References 100 publications

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“…Indeed, CLDN, OCLN and ZO proteins can be expressed at the basolateral membrane, in the cytoplasm and/or the nucleus where they have important functions in addition to those observed in TJs. For TJ proteins expressed at the basolateral membrane these non-canonical functions include endosomal trafficking, signalling and additional ion transport functions while TJ proteins in the nucleus have been shown to regulate gene transcription (reviewed in ref 16). Noteworthy, non-junctional TJ proteins do not diffuse in a random manner throughout the membrane.…”

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confidence: 99%

Tight junction proteins in gastrointestinal and liver disease

Zeisel

Dhawan

Baumert

2018

Gut

244

179

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Over the past two decades a growing body of evidence has demonstrated an important role of tight junction (TJ) proteins in the physiology and disease biology of GI and liver disease. On one side, TJ proteins exert their functional role as integral proteins of TJs in forming barriers in the gut and the liver. Furthermore, TJ proteins can also be expressed outside TJs where they play important functional roles in signalling, trafficking and regulation of gene expression. A hallmark of TJ proteins in disease biology is their functional role in epithelial-to-mesenchymal transition. A causative role of TJ proteins has been established in the pathogenesis of colorectal cancer and gastric cancer. Among the best characterised roles of TJ proteins in liver disease biology is their function as cell entry receptors for HCV—one of the most common causes of hepatocellular carcinoma. At the same time TJ proteins are emerging as targets for novel therapeutic approaches for GI and liver disease. Here we review our current knowledge of the role of TJ proteins in the pathogenesis of GI and liver disease biology and discuss their potential as therapeutic targets.

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confidence: 99%

Tight junction proteins in gastrointestinal and liver disease

Zeisel

Dhawan

Baumert

2018

Gut

244

179

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“…However, a surprising observation during the course of the study suggests that the lack of CAIX may not only interfere with epithelial pHi regulation, but actually result in a dramatic downregulation of the expression of claudin‐18A2. Claudin‐18 is by far the most abundant claudin expressed in the gastric mucosa and conveys the high resistance to protons 10, 12. Claudin‐18A2 was highly expressed in the newborn stomach, where CAIX was weakly expressed.…”

Section: Discussionmentioning

confidence: 99%

“…It has been recently established that a key element in conferring acid resistance to the gastric epithelium is the expression of the stomach‐specific claudin‐18 variants 18A2(1,2) 10. Claudin 18A2 is expressed in the same location as CAIX, namely the basolateral membranes with predilection in the surface and chief cell region 11, 12. Therefore, we have also addressed the expression of claudin‐18A2 in the gastric mucosa of the CAIX‐KO mice and their WT littermates during the critical phase in which the barrier function is compromised.…”

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confidence: 99%

Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin‐18 downregulation and acid backflux

Liu

Riederer

et al. 2017

Acta Physiologica

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AimThis study aimed to explore the molecular mechanisms for the parietal cell loss and fundic hyperplasia observed in gastric mucosa of mice lacking the carbonic anhydrase 9 (CAIX).MethodsWe assessed the ability of CAIX‐knockout and WT gastric surface epithelial cells to withstand a luminal acid load by measuring the pH i of exteriorized gastric mucosa in vivo using two‐photon confocal laser scanning microscopy. Cytokines and claudin‐18A2 expression was analysed by RT‐PCR.Results CAIX‐knockout gastric surface epithelial cells showed significantly faster pH i decline after luminal acid load compared to WT. Increased gastric mucosal IL‐1β and iNOS, but decreased claudin‐18A2 expression (which confer acid resistance) was observed shortly after weaning, prior to the loss of parietal and chief cells. At birth, neither inflammatory cytokines nor claudin‐18 expression were altered between CAIX and WT gastric mucosa. The gradual loss of acid secretory capacity was paralleled by an increase in serum gastrin, IL‐11 and foveolar hyperplasia. Mild chronic proton pump inhibition from the time of weaning did not prevent the claudin‐18 decrease nor the increase in inflammatory markers at 1 month of age, except for IL‐1β. However, the treatment reduced the parietal cell loss in CAIX‐KO mice in the subsequent months.ConclusionsWe propose that CAIX converts protons that either backflux or are extruded from the cells rapidly to CO 2 and H2O, contributing to tight junction protection and gastric epithelial pH i regulation. Lack of CAIX results in persistent acid backflux via claudin‐18 downregulation, causing loss of parietal cells, hypergastrinaemia and foveolar hyperplasia.

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“…(reviewed in Reference ). Apart from the function of claudins in regulating paracellular ion transport and membrane polarity at TJs, evidence indicates that they are also present at sites outside of the tight junction where they perform various noncanonical functions in cell signaling . They regulate cell proliferation, differentiation and gene expression in different cell types such as differentiation of bone cells osteoclasts and osteoblasts (reviewed in Reference ).…”

Section: Claudinsmentioning

confidence: 99%

Claudins in the brain: Unconventional functions in neurons

Tikiyani

Babu

2019

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Bonafide claudin proteins are functional and structural components of tight junctions and are largely responsible for barrier formation across epithelial and endothelial membranes. However, current advances in the understanding of claudin biology have revealed their unexpected functions in the brain. Apart from maintaining blood‐brain barriers in the brain, other functions of claudins in neurons and at synapses have been largely elusive and are just coming to light. In this review, we summarize the functions of claudins in the brain and their association in neuronal diseases. Further, we go on to cover some recent studies that show that claudins play signaling functions in neurons by regulating trafficking of postsynaptic receptors and controlling dendritic morphogenesis in the model organism Caenorhabditis elegans.

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Non-canonical functions of claudin proteins: Beyond the regulation of cell-cell adhesions

Cited by 78 publications

References 100 publications

Tight junction proteins in gastrointestinal and liver disease

Tight junction proteins in gastrointestinal and liver disease

Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin‐18 downregulation and acid backflux

Claudins in the brain: Unconventional functions in neurons

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