Abstract
Mucins are highly glycosylated proteins which protect the epithelium. In the small intestine, the goblet cell-secreted Muc2 mucin constitutes the main component of the loose mucus layer that traps luminal material. The transmembrane mucin Muc17 forms part of the carbohydrate-rich glycocalyx covering intestinal epithelial cells. Our study aimed at investigating the turnover of these mucins in the small intestine by using in vivo labeling of O-glycans with N-azidoacetylgalactosamine. Mice were injected intraperitoneally and sacrificed every hour up to 12 hours and at 24 hours. Samples were fixed with preservation of the mucus layer and stained for Muc2 and Muc17. Turnover of Muc2 was slower in goblet cells of the crypts compared to goblet cells along the villi. Muc17 showed stable expression over time at the plasma membrane on villi tips, in crypts and at crypt openings. In conclusion, we have identified different subtypes of goblet cells based on their rate of mucin biosynthesis and secretion. In order to protect the intestinal epithelium from chemical and bacterial hazards, fast and frequent renewal of the secreted mucus layer in the villi area is combined with massive secretion of stored Muc2 from goblet cells in the upper crypt.
Highlights
The small intestinal epithelium is constantly aiming to balance effective nutritional uptake with minimal damage due to exposure to ingested, secreted and resident agents
The small intestinal epithelium is renewed from the adult stem cells and a proliferative cell pool localized in the lower crypt
Using an in vivo labeling approach the GalNAc analogue GalNAz was incorporated during mucin biosynthesis, followed by visualization with a red fluorophore, added via a Click-iTTM reaction
Summary
The small intestinal epithelium is constantly aiming to balance effective nutritional uptake with minimal damage due to exposure to ingested, secreted and resident agents. Intestinal secreted mucus is a complex network built around multimers of the highly O-glycosylated MUC2 mucin[3,4], which is produced by specialized cells, the goblet cells (GCs). MUC17 features an extracellular sea-urchin sperm protein, enterokinase and agrin (SEA) domain located close to its transmembrane region This SEA domain is autocatalytically cleaved in the endoplasmic reticulum after which the two resulting parts remain linked by non-covalent bonds[14]. This generates a breakpoint, which likely acts as a mechanism to protect cell membranes from mechanical stress by detaching the large glycosylated extracellular part[15]. Turnover of the glycocalyx in general and MUC17 in particular are not yet understood, but it is to be expected that the dynamics of these molecules will impact their role and possible protective function
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