O-Linked Oligosaccharide Decoration of Proteins in the Production of Mucus - Essay Example

Since it is typical for mucin-related proteins to have tandem repeats rich with Ser/Thr residues, these amino acids become teeming with O-glycans. These areas in the glycoprotein are aptly called mucin-like domains. Mucin-related proteins can either be membrane-bound, in which case it is enclosing the cell or secreted to form the extracellular matrix (Tabak, 2010).

In the epithelium, such as those on the surface of the gastrointestinal wall, O-glyvans attached to epithelial cell membrane-bound mucin and its related proteins, mostly Muc2, constitute what is commonly called mucus. Mucin glycoproteins are made in enormous amounts by a specialized epithelial cell called the goblet cell. Physiologically, this cell is important in producing the inner mucus layer to replace the outer mucus layer used for bacterial clearance. To produce mucus, Muc2 should first be produced and secreted. They are prepared in the Golgi apparatus, in which the proteins are labeled for transport to the surface (Johansson, 2012). They can be compactly stored in large, regulated secretory mucin granules that can be found on the apical cytoplasm of goblet cells (Perez-Vilar, 2007)    

1. Importance of mucus

Mucus acts as a barrier from injurious elements to which the gut surface is commonly exposed, such as bacteria and mechanical forces. Microorganisms are trapped by the outer mucus layer for transport and excretion. Because fast turnover of mucus is necessary to be able to protect the gut from materials that regularly pass through the gut, secretion of Muc2 glycoproteins in the luminal surface epithelium occurs in just three hours after labeling in the Golgi apparatus. On the other hand, the goblet cells in the crypt epithelium store mucus in the mucin vesicles for 6 to 8 hours, before its contents can be released. In effect, new mucus is being secreted every hour (Johansson, 2012). Defect in mucus production occurs from lack of Muc2 production, Muc2 mutation, or inhibition of glucosyltransferases. Without mucus, bacteria attach to the epithelium, increase intestinal permeability, and raise the risk for colitis (Kim and Ho, 2010). Aside from the gastrointestinal systems, mucus also has a protective function in the respiratory, urogenital, ophalmologic, and auditory systems. Deregulation of its production or composition is implicated in chronic airway diseases, such as chronic obstructive pulmonary disease, asthma, and cystic fibrosis (Perez-Vilar, 2007). In cystic fibrosis, the alkalization due to the defective intracellular chloride channel caused defects in pH-sensitive glucosyltransferases. The abnormal glycoproteins produced by these defective enzymes also provide receptors for Pseudomonas (Al-Awqati, Barasch, and Landry, 1992).

        Role in cell signaling

The less common O-fucose glycans are attached by O-fucosyltransderase 1 and elongated by β 1,3N-acetylglucosaminyltransferases to epidermal growth factor-like (EGF) repeats of Notch protein. EGF repeats are approximately 40-amino acid-long cysteine-rich motifs, including a conserved six cysteine span that forms three conserved disulfide bonds. The sugar moiety modulates protein-protein interactions and downstream signaling. Notch is a membrane-bound signaling receptor important in differentiation. Elongation of O-fucose by Fringe limits Notch activation to the dorsal and ventral boundary, since it limits the binding of Notch with its ligands. Fringe defects result in segmentation and somitogenesis defects in mice. Similar to EGF repeats, Thrombospondin type 1 repeats (TSR) are made up of six conserved cysteines and three disulfide bonds and are modified with O-fucose glycans (Luther and Haltiwanger, 2009).   

1. Role in adenocarcinomas

Modification in mucin gene expression or its glycan structures has been implicated in intestinal cancers. Changes in glycan structures include shortening of the sugar moiety. Mucinous adenocarcinoma presents with excessive amounts of secreted mucins, representing more than 50% of the tumor bulk. In turn, the increase in Muc2 production is caused by alteration of epigenetic and genetic regulation of Muc2, such as via Muc2 promoter hypomethylation and increased transcription factor interaction. It usually occurs in the colon, and mucinous adenocarcinoma is 6-19% of all colorectal cancers. In the small intestine, it can mostly be found in the appendix. It is differentiated from signet-ring cell carcinoma, in which 50% of tumor cells are composed of intracytoplasmic mucin. Comparing the two, mucinous adenocarcinoma has a better prognosis than the other, although it can invade adjacent organs, such as lymph nodes and peritoneum (Kim and Ho, 2010).