Shunsuke Matsuda, Maika Miwa, Miki Tanabe, Mao Kobayashi, Shokoku Shu, Yuta Yoshino, Norihiro Tada, Akichika Itoh, Akira Ikari
{"title":"Sirtuin-2 Is Involved in the Regulation of Claudin-4 Expression and Paracellular Barrier Function in Keratinocytes","authors":"Shunsuke Matsuda, Maika Miwa, Miki Tanabe, Mao Kobayashi, Shokoku Shu, Yuta Yoshino, Norihiro Tada, Akichika Itoh, Akira Ikari","doi":"10.1002/jcb.70027","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>Claudin-1 (CLDN1) and CLDN4 are highly expressed in keratinocytes and may function as a paracellular barrier to water and small molecules. The physiological function of CLDN4 has not been fully understood, whereas dysfunction of CLDN1 is involved in the pathophysiology of allergy and inflammatory diseases. Here, we found that the protein level of CLDN4 in the skin tissues of 36-week-old mice was lower than that in 6-week-old mice. In contrast, there was not much difference in the mRNA levels of <i>CLDN4</i>. Tenovin-1 (Ten-1), a sirtuin-1/2 inhibitor, decreased the protein level of CLDN4 without affecting that of CLDN1 in human keratinocyte-derived HaCaT cells. The decrease in <i>CLDN4</i> mRNA by Ten-1 was much less than that in protein. Cycloheximide-chase assay showed that the protein stability of CLDN4 was attenuated by Ten-1. The Ten-1-induced decrease in CLDN4 protein was inhibited by clathrin-dependent endocytosis and proteasome inhibitors. The Ten-1 treatment or SIRT2 silencing induced the elevation of acetylated CLDN4 protein, leading to the reduction of CLDN4 protein. In addition, the paracellular barrier function was reduced by Ten-1 treatment or SIRT2 silencing. These results indicate that Ten-1 may enhance the clathrin-dependent endocytosis and proteasome-dependent degradation of CLDN4 protein, resulting in the dysfunction of paracellular barrier. The Ten-1-induced reduction of CLDN4 protein and paracellular barrier function were inhibited by curcumin, a polyphenol contained in <i>Curcuma longa</i> plant. We suggest that the reduction of CLDN4 protein in keratinocytes may be involved in the age-related dysfunction of the skin barrier, which may be rescued by curcumin.</p>\n </div>","PeriodicalId":15219,"journal":{"name":"Journal of cellular biochemistry","volume":"126 3","pages":""},"PeriodicalIF":3.0000,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of cellular biochemistry","FirstCategoryId":"99","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jcb.70027","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Claudin-1 (CLDN1) and CLDN4 are highly expressed in keratinocytes and may function as a paracellular barrier to water and small molecules. The physiological function of CLDN4 has not been fully understood, whereas dysfunction of CLDN1 is involved in the pathophysiology of allergy and inflammatory diseases. Here, we found that the protein level of CLDN4 in the skin tissues of 36-week-old mice was lower than that in 6-week-old mice. In contrast, there was not much difference in the mRNA levels of CLDN4. Tenovin-1 (Ten-1), a sirtuin-1/2 inhibitor, decreased the protein level of CLDN4 without affecting that of CLDN1 in human keratinocyte-derived HaCaT cells. The decrease in CLDN4 mRNA by Ten-1 was much less than that in protein. Cycloheximide-chase assay showed that the protein stability of CLDN4 was attenuated by Ten-1. The Ten-1-induced decrease in CLDN4 protein was inhibited by clathrin-dependent endocytosis and proteasome inhibitors. The Ten-1 treatment or SIRT2 silencing induced the elevation of acetylated CLDN4 protein, leading to the reduction of CLDN4 protein. In addition, the paracellular barrier function was reduced by Ten-1 treatment or SIRT2 silencing. These results indicate that Ten-1 may enhance the clathrin-dependent endocytosis and proteasome-dependent degradation of CLDN4 protein, resulting in the dysfunction of paracellular barrier. The Ten-1-induced reduction of CLDN4 protein and paracellular barrier function were inhibited by curcumin, a polyphenol contained in Curcuma longa plant. We suggest that the reduction of CLDN4 protein in keratinocytes may be involved in the age-related dysfunction of the skin barrier, which may be rescued by curcumin.
期刊介绍:
The Journal of Cellular Biochemistry publishes descriptions of original research in which complex cellular, pathogenic, clinical, or animal model systems are studied by biochemical, molecular, genetic, epigenetic or quantitative ultrastructural approaches. Submission of papers reporting genomic, proteomic, bioinformatics and systems biology approaches to identify and characterize parameters of biological control in a cellular context are encouraged. The areas covered include, but are not restricted to, conditions, agents, regulatory networks, or differentiation states that influence structure, cell cycle & growth control, structure-function relationships.