Claudin-5 Affects Endothelial Autophagy in Response to Early Hypoxia

Yu, Ping; Li, Yanyu; Zhong, Gaoliang; Li, Wen; Chen, Bing; Zhang, Jingjing

doi:10.3389/fphys.2021.737474

Cited by 15 publications

(10 citation statements)

References 37 publications

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“…It is well known that two intracellular degradation pathways are responsible for the degradation of most proteins in eukaryotic cells, autophagy and UPS [18–20]. Meanwhile, our recent studies have also revealed bidirectional regulations of the dynamic of claudin‐5 and autophagic activation [21]. Based on these, we questioned the potential correlations between intracellular degradation of claudin‐5 and autophagy.…”

Section: Resultsmentioning

confidence: 98%

Autophagic degradation of claudin‐5 mediated by its binding to a Clostridium perfringens enterotoxin fragment modulates endothelial barrier permeability

Lin

Tan

et al. 2022

FEBS Letters

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The blood‐brain barrier (BBB) protects the central nervous system (CNS) from harmful elements, while it also restricts efficient drug delivery into the CNS. Previously, we generated a mutated fragment of Clostridium perfringens enterotoxin (cCPEYWSH) which specifically binds to the endothelial tight junction protein claudin‐5. Here, we explore the mechanisms regulating the dynamics of membranous claudin‐5 and BBB permeability. Following cCPEYWSH binding to claudin‐5, caveolin‐1 mediates the redistribution of claudin‐5 to the cytosol. This abnormal cytosolic aggregation triggers the autophagic degradation of claudin‐5, leading to an increase in BBB permeability. Enhancement or inhibition of autophagy accelerates or inhibits the degradation of cytosolic claudin‐5, respectively. Our findings may pave the way for improving BBB permeability for drug delivery.

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Section: Resultsmentioning

confidence: 98%

Autophagic degradation of claudin‐5 mediated by its binding to a Clostridium perfringens enterotoxin fragment modulates endothelial barrier permeability

Lin

Tan

et al. 2022

FEBS Letters

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“…There are limited reports on the effects of CLDNs-mediated autophagy. It was reported that CLDN5 knockout decreased autophagy in endothelial cells after hypoxia induction [ 37 ]. Wu et al found that CLDN1 upregulation significantly increased autophagy flux in esophageal squamous carcinoma cells [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

CLDN6 inhibits breast cancer metastasis through WIP-dependent actin cytoskeleton-mediated autophagy

Dong

Qiu

Sun

et al. 2023

J Exp Clin Cancer Res

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Background As a breast cancer suppressor gene, CLDN6 overexpression was found to inhibit breast cancer metastasis in our previous studies, but the specific mechanism remains unclear. This study aimed to clarify the role and mechanism of CLDN6 in inhibiting breast cancer metastasis. Methods Western blot, immunofluorescence and transmission electron microscopy were performed to detect autophagy. Wound healing, transwell assays and lung metastasis mouse models were used to examine breast cancer metastasis. Phalloidin staining and immunofluorescent staining were used to observe actin cytoskeleton. mRNA seq, RT-PCR, western blot, chromatin immunoprecipitation, dual luciferase reporter assay, co-immunoprecipitation and immunofluorescence were performed to define the molecular mechanism. The expression levels and clinical implication of CLDN6, WIP and LC3 in breast cancer tissues were evaluated using immunohistochemistry. Results We demonstrated that CLDN6 inhibited breast cancer metastasis through autophagy in vitro and vivo. We unraveled a novel mechanism that CLDN6 regulated autophagy via WIP-dependent actin cytoskeleton assembly. Through its PDZ-binding motif, overexpressed CLDN6 interacted with JNK and upregulated JNK/c-Jun pathway. C-Jun promoted WIP expression at the transcriptional level. Notably, we observed c-Jun transcriptionally upregulated CLDN6 expression, and there was a positive feedback loop between CLDN6 and JNK/c-Jun. Finally, we found that CLDN6, WIP and LC3 expression correlated with each other, and WIP expression was significantly associated with lymph node metastasis of breast cancer patients. Conclusions The data provide a new insight into the inhibitory effects of CLDN6-mediated autophagy on breast cancer metastasis, and revealed the new mechanism of CLDN6 regulating autophagy through WIP-dependent actin cytoskeleton. Our findings enrich the theoretical basis for CLDN6 as a potential biomarker for breast cancer diagnosis and therapy.

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“…MDCK-II transfectants expressing mammalian CLDN5 could strengthen the paracellular barrier [ 50 ]. Moreover, the loss of CLDN5 results in the leakage of the BBB in vivo and in vitro [ 19 , 51 ]. Here, although the transfections of zebrafish-specific cldn5a into in vitro cells were missing, we verified that mammalian CLDN5 is required for establishing both epithelial and endothelial barriers in multiple cell models, consistent with its canonical sealing functions reported (Additional file 1 : Fig.…”

Section: Discussionmentioning

confidence: 99%

Claudin-5a is essential for the functional formation of both zebrafish blood-brain barrier and blood-cerebrospinal fluid barrier

Wang

Zhang

et al. 2022

Fluids Barriers CNS

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Background Mammalian Claudin-5 is the main endothelial tight junction component maintaining blood-brain barrier (BBB) permeability, while Claudin-1 and -3 seal the paracellular space of choroid plexus (CP) epithelial cells contributing to the blood-cerebrospinal fluid barrier (BCSFB). In zebrafish, two paralogs of claudin-5a and -5b are expressed while their roles in the formation of BBB and BCSFB are unclear. Methods The expression patterns of Claudin-5a and -5b in zebrafish brains were systematically analyzed by immunofluorescence (IF) assay. The developmental functions of Claudin-5a and -5b were characterized by generating of claudin-5a and -5b mutants respectively. Meanwhile, the cerebral inflammation and cell apoptosis in claudin-5a-/- were assessed by live imaging of transgenic zebrafish, RT-qPCR, IF, and TUNEL assay. The integrity of BBB and BCSFB was evaluated by in vivo angiographic and dye permeation assay. Finally, RT-qPCR, whole-mount RNA in situ hybridization (WISH), and transmission electron microscopy (TEM) analyses were performed to investigate the development of cerebral vessels and choroid plexus. Results We showed that Claudin-5a and -5b are both expressed in zebrafish cerebrovascular endothelial cells (ECs). In addition, Claudin-5a was strongly expressed in CP epithelial cells. Loss of Claudin-5b showed no effect on zebrafish vasculogenesis or BBB function. In contrast, the knockout of claudin-5a caused a lethal phenotype of severe whole-brain oedema, ventricular dilatation, and cerebral hernia in zebrafish larvae, although the cerebral vasculogenesis and the development of CP were not altered. In claudin-5a-/- , although ultrastructural analysis of CP and cerebral capillary showed intact integrity of epithelial and endothelial tight junctions, permeability assay indicated a disruption of both BBB and BCSFB functions. On the molecular level, it was found that ZO-1 was upregulated in the CP epithelium of claudin-5a-/-, while the notch and shh pathway responsible for CP development was not affected due to loss of Claudin-5a. Conclusions Our findings verified a non-functional role of zebrafish Claudin-5b in the BBB and identified Claudin-5a as the ortholog of mammalian Claudin-5, contributing to the development and the functional maintenance of both BBB and BCSFB.

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Claudin-5 Affects Endothelial Autophagy in Response to Early Hypoxia

Cited by 15 publications

References 37 publications

Autophagic degradation of claudin‐5 mediated by its binding to a Clostridium perfringens enterotoxin fragment modulates endothelial barrier permeability

Autophagic degradation of claudin‐5 mediated by its binding to a Clostridium perfringens enterotoxin fragment modulates endothelial barrier permeability

CLDN6 inhibits breast cancer metastasis through WIP-dependent actin cytoskeleton-mediated autophagy

Claudin-5a is essential for the functional formation of both zebrafish blood-brain barrier and blood-cerebrospinal fluid barrier

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