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 TNFα 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.
Highlights
The apical surface of intestinal enterocytes is covered by a dense and heavily glycosylated glycocalyx that extends up to one micrometer from the cell membrane into the lumen
MUC3, MUC12 and MUC17 belong to the group of sea-urchin sperm protein, enterokinase and agrin (SEA) type transmembrane mucins due to their extracellular SEA domain between the mucin domain and the single-span transmembrane domain, which is followed by a cytoplasmic tail (CT) domain [3, 4]
The transmembrane mucin MUC17 together with MUC3, MUC12 and MUC13 constitutes an integral component of the epithelial cell glycocalyx
Summary
The apical surface of intestinal enterocytes is covered by a dense and heavily glycosylated glycocalyx that extends up to one micrometer from the cell membrane into the lumen. The transmembrane mucins MUC3, MUC12 and MUC17 are clustered in the same genomic locus, 7q22. They contain a heavily O-glycosylated proline threonine serine (PTS)-rich domain that forms the extended extracellular mucin domain [2]. The SEA domain is known to be autocatalytically cleaved during protein folding in the endoplasmic reticulum, rendering a mature transmembrane mucin heterodimer which is inserted into the apical plasma membrane [5]. The SEA domain unfolds when mechanical forces are applied to the transmembrane mucin. The exact function of the SEA domain remains yet to be defined [6]
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