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Desmoglein 2 Regulates the Intestinal Epithelial Barrier via p38 Mitogen‐Activated Protein Kinase
Author(s) -
Ungewiß Hanna,
Vielmuth Franziska,
Suzuki Shintaro T.,
Maiser Anderas,
Harz Hartmann,
Leonhardt Heinrich,
Kugelmann Daniela,
Schlegel Nicolas,
Waschke Jens
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.465.4
Subject(s) - adherens junction , microbiology and biotechnology , desmoglein , barrier function , chemistry , cadherin , tight junction , cell junction , biology , biochemistry , cell
Intestinal epithelial barrier properties are maintained by a junctional complex consisting of tight junctions (TJ), adherens junctions (AJ) and desmosomes. Desmoglein 2 (Dsg2), an adhesion molecule of desmosomes, is required for epithelial barrier properties and may contribute to barrier defects in Crohn's disease. Here, for the first time we identified extra desmosomal Dsg2 on the surface of differentiated enterocytes displaying junctional complexes by Triton extraction, confocal microscopy, SIM and STED. Atomic force microscopy (AFM) revealed Dsg2‐specific binding events on the surface of enterocytes with a mean unbinding force of around 30 pN which were more prominent close to cell borders. Furthermore, we demonstrated that inhibition of Dsg2 binding induced activation of p38 mitogen‐activated protein kinase (p38MAPK) which is a key regulator of desmosomal adhesion. An inhibitory Dsg2 antibody activated p38MAPK, under conditions where it significantly reduced cell cohesion in a dissociation assay and Dsg2‐specific binding in AFM. Loss of Dsg2 in enterocytes led to reduced p38MAPK activity accompanied with loss of barrier integrity and impaired barrier reformation. Dsc2 rescue in Dsg2/Dsc2 deficient enterocytes did not restore p‐p38MAPK levels indicating, that Dsg2 regulates the activity of this kinase. Direct activation of p38MAPK in Dsg2 knockout cells enhanced barrier reformation demonstrating that Dsg2‐mediated activation of p38MAPK is crucial for barrier function. Collectively, our data show that Dsg2, in addition to its adhesion function, regulates intestinal barrier function via p38MAPK signaling. Support or Funding Information This work was supported by the DFG priority program SPP 1782