Pelaseyed, T. | Search bioRxiv

bioRxiv2023

The MYO1B and MYO5B motor proteins and the SNX27 sorting nexin regulate membrane mucin MUC17 trafficking in enterocytes

A dense glycocalyx, composed of the megaDalton-sized membrane mucin MUC17, coats the microvilli in the apical brush border of transporting intestinal epithelial cells, called enterocytes. The establishment of the MUC17-based glycocalyx in the mouse small intestine occurs at the critical suckling-weaning transition. The enterocytic glycocalyx extends 1 {micro}m into the intestinal lumen and prevents the gut bacteria from directly attaching to the enterocytes. To date, the mechanism behind apical targeting of MUC17 to the brush border remains unknown. Here, we show that the actin-based motor proteins MYO1B and MYO5B, and the sorting nexin SNX27 regulate the intracellular trafficking of MUC17 in enterocytes. We demonstrate that MUC17 turnover at the brush border is slow and controlled by MYO1B and SNX27. Furthermore, we report that MYO1B regulates MUC17 protein levels in enterocytes, whereas MYO5B specifically governs MUC17 levels at the brush border. Together, our results extend our understanding of the intracellular trafficking of membrane mucins and provide mechanistic insights into how defective trafficking pathways render enterocytes sensitive to bacterial invasion.

cell biology↗

bioRxiv2022

Discovery of a MUC3B gene reconstructs the membrane mucin gene cluster on human chromosome 7

Human tissue surfaces are coated with mucins, a family of macromolecular sugar-laden proteins serving diverse functions from lubrication to formation of selective biochemical barriers against harmful microorganisms and molecules. Membrane mucins are a distinct group of mucins that are attached to epithelial cell surfaces where they create a dense glycocalyx facing the extracellular environment. All mucin proteins carry long stretches of tandemly repeated sequences that undergo extensive O-linked glycosylation to form linear mucin domains. However, the repetitive nature of mucin domains makes them prone to recombination and render their genetic sequences particularly difficult to read with standard sequencing technologies. As a result, human mucin genes suffer from significant sequence gaps that have hampered investigation of gene function in health and disease. Here we leveraged a recent human genome assembly to identify a previously unmapped MUC3B gene located within a cluster of four structurally related membrane mucin genes that we entitle the MUC3 cluster at q22 locus in chromosome 7. We found that MUC3B shares high sequence identity with the known MUC3A gene, and that the two genes are governed by evolutionarily conserved regulatory elements. Furthermore, we show that MUC3A, MUC3B, MUC12 and MUC17 in the human MUC3 cluster are exclusively expressed in intestinal epithelial cells. Our results complete existing genetic gaps in the MUC3 cluster that is a conserved genetic unit during primate evolution. We anticipate our results to be the starting point for detection of new polymorphisms in the MUC3 cluster associated with human diseases. Moreover, our study provides the basis for exploration of intestinal mucin gene function in widely used experimental models such as human intestinal organoids and genetic mouse models.

genetics↗