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The human transmembrane mucin MUC17 responds to TNF alpha by increased presentation at the plasma membrane

Journal article
Authors Hannah Schneider
Evelin Berger
Brendan Dolan
Beatriz Martinez Abad
Liisa Arike
Thaher Pelaseyed
Gunnar C. Hansson
Published in Biochemical Journal
Volume 476
Pages 2281-2295
ISSN 0264-6021
Publication year 2019
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 2281-2295
Language en
Links dx.doi.org/10.1042/bcj20190180
Keywords epithelial-cells, helicobacter-pylori, gene-expression, lipid rafts, sea, domain, phosphorylation, barrier, exosomes, recruitment, receptor, Biochemistry & Molecular Biology
Subject categories Microbiology in the medical area

Abstract

Transmembrane mucin MUC17 is an integral part of the glycocalyx as it covers the brush border membrane of small intestinal enterocytes and presents an extended O-glycosylated mucin domain to the intestinal lumen. Here, we identified two unknown phosphorylated serine residues, S4428 and S4492, in the cytoplasmic tail of human MUC17. We have previously demonstrated that MUC17 is anchored to the apical membrane domain via an interaction with the scaffolding protein PDZK1. S4492, localized in the C-terminal PDZ binding motif of MUC17, was mutated to generate phosphomimetic and phosphodeficient variants of MUC17. Using Caco-2 cells as a model system, we found that induction of an inflammatory state by long-term stimulation with the proinflammatory cytokine TNF alpha resulted in an increase of MUC17 protein levels and enhanced insertion of MUC17 and its two phospho-variants into apical membranes. Up-regulation and apical insertion of MUC17 was followed by shedding of MUC17-containing vesicles. Transmembrane mucins have previously been shown to play a role in the prevention of bacterial colonization by acting as sheddable decoys for encroaching bacteria. Overexpression and increased presentation at the plasma membrane of wild-type MUC17 and its phosphodeficient variant MUC17 S-4492A protected Caco-2 cells against adhesion of enteropathogenic Escherichia coli, indicating that C-terminal phosphorylation of MUC17 may play a functional role in epithelial cell protection. We propose a new function for MUC17 in inflammation, where MUC17 acts as a second line of defense by preventing attachment of bacteria to the epithelial cell glycocalyx in the small intestine.

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