LAUSR

Airways have a mucus lining that protects the lungs from the deleterious effects of exposure to inhaled particles, pathogens, and gases. Airway mucus is a gel in which the polymer network consists of heavily glycosylated mucins and the swelling agent is water. Glycosylation extends the mucin polypeptide in solution, and cross-linking of mucin polymers imparts to the airway mucus hydrogel its solid structure and adhesive tack. The relatively low elasticity of the airway mucus gel in health is tuned to enable ease of transport by the mucociliary escalator. Airway mucus gel pathology is a feature of multiple lung diseases, and relatively few treatments target this pathology. Among mechanisms of pathologic mucus gel formation, abnormalities in mucin gene expression are important and potentially treatable. Mucins have the gene symbol MUC followed by a number, and MUC5AC and MUC5B are the principal secreted gelforming mucins in airway mucus. In contrast, MUC5B and MUC7 mucins predominate in saliva, and MUC5AC and MUC6 mucins predominate in gastric secretions. MUC5AC is secreted exclusively by goblet cells in the airway epithelium, and MUC5B is secreted by both goblet cells and mucus cells in submucosal gland (SMG) acini (Figure 1A) (1). The genes encoding MUC5AC andMUC5B are located on chromosome 11p15, and their genomic structure consists of a single large exon encoding a complex multidomain protein. Although the protein structures of MUC5AC and MUC5B are broadly similar, there are differences in how the mucin domains are organized (Figure 1B). Deletion of muc5ac in mice does not cause a noticeable airway phenotype, except that muc5ac-deficient mice are protected from allergen-induced airway mucus plugging and airway hyperresponsiveness (2). In contrast, deletion of muc5b results in airway infection with Staphylococcus aureus, impaired mucus transport, and accumulation of neutrophils, eosinophils, and macrophages (3). These murine studies reveal a distinct role for MUC5B in host defense of the lungs. In this issue of the Journal, Costain and colleagues (pp. 761–768) report on a family with hereditary MUC5B deficiency because of a genetic variant inMUC5B that results in a truncatedMUC5BmRNA and a failure to translate MUC5B protein (4). Two sisters with MUC5B deficiency had histories of repeated S. aureus airway infections since childhood, and they both had impaired mucociliary transport, low lung function, and bronchiectasis. Interestingly, cytologic analysis of sputum from the MUC5B-deficient patients revealed neutrophilia and increased numbers of apoptotic macrophages. All of these findings closely mirror the phenotype ofmuc5b mice and provide strong support for a critical role for MUC5B in controlling infections in the airways and maintaining immune homeostasis in the lungs. The mechanisms by whichMUC5B selectively protects the airways from infection are unclear. One possibility is that MUC5B directly inhibits microbial growth or survival. AlthoughMUC6 inhibits growth ofHelicobacter pylori andMUC5AC inhibits survival of Trichuris muris (5, 6), neither MUC5AC norMUC5B inhibits growth of S. aureus (3). Another possibility is that MUC5B is a scaffold for antimicrobial molecules. Sialylation and sulfation of mucin glycans impart negative charges that promote electrostatic interactions with cationic proteins, and epitopes presented by mucin glycans in the mucus gel allow interactions with lectins. It is not known if MUC5B has specific glycan features that generate a mucin interactome peculiarly well suited to airway defense. Finally, it is possible that MUC5B polymers generate mucus gels that more efficiently clear particles from the airways. MUC5AC forms tightly organized networks with a high degree of branching and is secreted by goblet cells as wispy threads (7, 8). In contrast, MUC5B is secreted from SMG ducts in the form of filaments that bind to inhaled particles to facilitate their clearance. Thus, despite similar protein architecture, MUC5B andMUC5AC appear to form specific types of mucus gel structures that may have specific particle clearance functions. It is possible that cells that secrete MUC5B (goblet cells and SMGmucus cells) or MUC5AC (goblet cells) determine the mucin-specific mucus gel structure. Recent studies in pigs that lack airway SMGs show that their airway surface liquid has a reduced ability to kill S. aureus and other bacteria (9). SMGs produce multiple antimicrobial peptides and also regulate mucus gel hydration and pH, but it may be that MUC5B secretion by mucus cells in SMGs is a critical component of SMG-mediated bacterial defense. So evidence is accumulating that MUC5B forms gel structures important for microbial defense, but too muchMUC5Bmay not be a good thing. For example, whereas chronic upregulation of MUC5AC is associated with airway mucus plugging and airflow obstruction (10, 11), upregulation of MUC5B (through a gene polymorphism in its promotor) is associated with pulmonary fibrosis (12). The mechanism of MUC5B-mediated lung fibrosis is not well understood, but the association has emphasized the multiple ways in which mucins are involved in mucociliary clearance, inflammatory cell turnover, and epithelial mesenchymal signaling. The clinical phenotype of the MUC5B-deficient patients described by Costain and colleagues informs knowledge of lung biology and contains surprises about oral biology. For example, the complete absence of MUC5B did not preclude lung This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern ([email protected]).