Desmoglein2 Regulates Claudin2 Expression by Sequestering PI-3-Kinase in Intestinal Epithelial Cells

Please always quote using this URN: urn:nbn:de:bvb:20-opus-247059
  • Inflammation-induced reduction of intestinal desmosomal cadherin Desmoglein 2 (Dsg2) is linked to changes of tight junctions (TJ) leading to impaired intestinal epithelial barrier (IEB) function by undefined mechanisms. We characterized the interplay between loss of Dsg2 and upregulation of pore-forming TJ protein Claudin2. Intraperitoneal application of Dsg2-stablising Tandem peptide (TP) attenuated impaired IEB function, reduction of Dsg2 and increased Claudin2 in DSS-induced colitis in C57Bl/6 mice. TP blocked loss of Dsg2-mediated adhesionInflammation-induced reduction of intestinal desmosomal cadherin Desmoglein 2 (Dsg2) is linked to changes of tight junctions (TJ) leading to impaired intestinal epithelial barrier (IEB) function by undefined mechanisms. We characterized the interplay between loss of Dsg2 and upregulation of pore-forming TJ protein Claudin2. Intraperitoneal application of Dsg2-stablising Tandem peptide (TP) attenuated impaired IEB function, reduction of Dsg2 and increased Claudin2 in DSS-induced colitis in C57Bl/6 mice. TP blocked loss of Dsg2-mediated adhesion and upregulation of Claudin2 in Caco2 cells challenged with TNFα. In Dsg2-deficient Caco2 cells basal expression of Claudin2 was increased which was paralleled by reduced transepithelial electrical resistance and by augmented phosphorylation of AKT\(^{Ser473}\) under basal conditions. Inhibition of phosphoinositid-3-kinase proved that PI-3-kinase/AKT-signaling is critical to upregulate Claudin2. In immunostaining PI-3-kinase dissociated from Dsg2 under inflammatory conditions. Immunoprecipitations and proximity ligation assays confirmed a direct interaction of Dsg2 and PI-3-kinase which was abrogated following TNFα application. In summary, Dsg2 regulates Claudin2 expression by sequestering PI-3-kinase to the cell borders in intestinal epithelium.show moreshow less

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Metadaten
Author: Natalie Burkard, Michael Meir, Felix Kannapin, Christoph Otto, Maximilian Petzke, Christoph-Thomas Germer, Jens Waschke, Nicolas Schlegel
URN:urn:nbn:de:bvb:20-opus-247059
Document Type:Journal article
Faculties:Medizinische Fakultät / Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I)
Language:English
Parent Title (English):Frontiers in Immunology
ISSN:1664-3224
Year of Completion:2021
Volume:12
Article Number:756321
Source:Frontiers in Immunology (2021) 12:756321. doi: 10.3389/fimmu.2021.756321
DOI:https://doi.org/10.3389/fimmu.2021.756321
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:Claudin2; Dsg2; PI-3-kinase; desmosome; inflammation; inflammatory bowel disease; intestinal barrier; tight junction
Release Date:2022/02/11
Date of first Publication:2021/09/30
Open-Access-Publikationsfonds / Förderzeitraum 2021
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International