ABSTRACT
The respiratory tract mucosa is constantly bombarded with microorganisms as well as other extraneous material and is thus a major potential site for infection and the entry of foreign antigens into the body. Normally, mucosal protection is provided by a surface “ ectomatrix,” the airway epithelial cell layer and the mucosal immune system in the submucosal connective tissue. The ectomatrix is composed of cell-associated glycoproteins and secreted mucins forming a “ gly-cocalyx” and a mucus gel, respectively. The latter interacts with the cilia to form the mucocilliary transport system. In addition, many proteins involved in host defense such as secretory IgA, lysozyme, lactoferrin, and P-defensins are enriched at the respiratory tract surface. The wide variety of protective agents at the mucosal surface would appear to allow for a degree of adaptability to changing requirements, but how the different components interact to provide optimal protection under different circumstances is currently poorly understood. The focus of this review is on the large mucus-forming mucins, although the cell-associated ones will also be considered. 167
Mucins are characterized by the presence of highly glycosylated “ mucin-like domains,” and under the broadest definition the family contains both secreted and transmembrane glycoproteins including selectin ligands and glycophorin (1). However, 13 genes encoding molecules with mucin domains are so far considered to belong to the mucin family. These, designated MUC1-MUC4, MUC5AC, MUC5B, MUC6-MUC12, are numbered in order of their description. Although the apoproteins encoded by the genes differ significantly in structure, each contains one or several regions rich in serine and/or threonine residues to which large numbers of oligosaccharide side chains are attached via O-glycosidic bonds. The mucin domains often contain tandemly repeated amino acid sequences that appear to be unique for each mucin. The number of repeats within the tandem repeat regions, and thus the total lengths of the glycosylated regions, vary between individuals, and this is referred to as VNTR polymorphism. The complete sequences for MUC1, MUC2, MUC4, MUC5B, and MUC7 (2-8) and large stretches of MUC5AC (9-12), as well as the C-terminal sequences of MUC3 and MUC6 (13-15), are now known. On the basis of their structures, MUC2, MUC5AC, MUC5B, and MUC6 are predicted to be “ oligomeric” mucins, while MUC1, MUC3, MUC4, and MUC7 are considered to be monomeric species. Most of the latter appear to be membrane-bound. The MUC2, MUC5AC, and MUC5B mucins contain cysteine-rich domains in the C-and N-terminal regions with sequence homologies to each other as well as to the D-domains of the von Willebrand factor (vWF). The genes encoding these mucins, as well as that coding for the MUC6 mucin, are found as a gene cluster on chromosome lip 15.5 and are thought to have arisen from a common ancestral gene (12,16).The deduced sequences for the MUC1, MUC3, and MUC4 mucin apoproteins indicate the presence of transmembrane domains but lack cysteine-rich domains with homology to those in the mucus-forming mucins, and they are thus predicted to be cell-associated, monomeric structures. Recently, two “ novel” mucin cDNAs encoding molecules with transmembrane domains {MUCH and MUC12) have been identified, and both co-localize with MUC3 on chromosome 7q22 suggesting the presence of a cluster of cell-associated mucin genes in this region (17,18). MUC7 is a monomeric, secreted mucin.In situ hybridization and/or immunohistochemistry have revealed the expression of MUC1, MUC2, MUC4, MUC5AC, MUC5B, MUC7, and MUC8 genes in the airways (19-23). MUC2 and MUC5AC are expressed in the epithelial goblet cells, MUC1 and MUC4 in the epithelial ciliated cells, and MUC5B, MUC7, and MUC8 are associated with the submucosal glands. Northern blotting has also indicated MUCH expression in the lungs (17).
