Goblet cells need some stress

Mucus is vital for the protection of epithelial surfaces in the body. It assists in numerous functions to maintain homeostasis, acting as a selective physical barrier that traps and transports unwanted components. In the colon, mucus forms a barrier both dependent on and impenetrable to bacteria, tightly linking the mucus system with the microbiota (1, 2). At the same time, mucus provides a nutritional source for the microbiota. Diseases such as ulcerative colitis (UC), in which mucus protection fails, result in epithelial cells having increased bacterial exposure (3). In cystic fibrosis, abnormally attached mucus of the small intestine leads to bacterial overgrowth (4, 5), which is similar to the phenotype observed in many lung diseases.

Mucus is produced and secreted by the highly specialized cells of the secretory lineage, the goblet cells. These cells have been considered uninteresting and homogeneous, but recent single-cell information shows dramatic variability (6, 7). Mucins are the main structural element of mucus and they, as well as some of the other abundant mucus proteins, are large proteins that are extensively disulphide stabilized, oligomeric, and highly glycosylated. The mucins are sorted and stored in large granules before being secreted. Producing large quantities of mucins is challenging for the cell and especially the endoplasmic reticulum (ER), which requires specific molecules to cope with folding and forming correct disulphide bonds. This demand makes the goblet cells specifically vulnerable to ER overloading. Healthy cells respond to biosynthetic overload through the ER stress pathway known as the unfolded protein response (UPR), comprising three branches that (a) alleviate protein misfolding, (b) reduce protein synthesis, and (c) enhance unfolded protein degradation (8). If accumulated misfolded protein amounts are large and restoration is not achieved, the cell becomes destined for apoptosis. One of the ER stress branches, as observed in most cells including enterocytes, uses the sensor ERN1 (also called IRE1α), which signals via XBP1 to induce ER-associated degradation (ERAD) and increase expression of ER proteins assisting in folding. In addition, ERAD limits translation by degrading mRNA by regulated ERN1-dependent mRNA decay. Interestingly, all goblet cells have an additional closely related molecule, ERN2 (also called IRE1β), not found in most other cells. Its specific expression indicates a distinct function in goblet cells, likely to handle mucin protein folding. Grey et al. have previously shown that ERN2 binds ERN1 to limit the ER stress responses (9). This observation indicated that ERN2 might regulate ER function in goblet cells.

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