Respiratory Tract Mucin Genes and Mucin Glycoproteins in Health and Disease

Abstract

This review focuses on the role and regulation of mucin glycoproteins (mucins) in airway health and disease. Mucins are highly glycosylated macromolecules (≥50% carbohydrate, wt/wt). MUC protein backbones are characterized by numerous tandem repeats that contain proline and are high in serine and/or threonine residues, the sites of O-glycosylation. Secretory and membrane-tethered mucins contribute to mucociliary defense, an innate immune defense system that protects the airways against pathogens and environmental toxins. Inflammatory/immune response mediators and the overproduction of mucus characterize chronic airway diseases: asthma, chronic obstructive pulmonary diseases (COPD), or cystic fibrosis (CF). Specific inflammatory/immune response mediators can activate mucin gene regulation and airway remodeling, including goblet cell hyperplasia (GCH). These processes sustain airway mucin overproduction and contribute to airway obstruction by mucus and therefore to the high morbidity and mortality associated with these diseases. Importantly, mucin overproduction and GCH, although linked, are not synonymous and may follow from different signaling and gene regulatory pathways. In section i, structure, expression, and localization of the 18 human MUC genes and MUC gene products having tandem repeat domains and the specificity and application of MUC-specific antibodies that identify mucin gene products in airway tissues, cells, and secretions are overviewed. Mucin overproduction in chronic airway diseases and secretory cell metaplasia in animal model systems are reviewed in section ii and addressed in disease-specific subsections on asthma, COPD, and CF. Information on regulation of mucin genes by inflammatory/immune response mediators is summarized in section iii. In section iv, deficiencies in understanding the functional roles of mucins at the molecular level are identified as areas for further investigations that will impact on airway health and disease. The underlying premise is that understanding the pathways and processes that lead to mucus overproduction in specific airway diseases will allow circumvention or amelioration of these processes.

The cell surface mucin MUC1 limits the severity of influenza A virus infection

“…Understanding the MUC1 regulatory mechanisms in the context of IAV infection is of obvious interest to our future studies and may lead to an understanding of the mechanism as to why IAV infection is as a major trigger for disease exacerbations in patients with chronic respiratory illnesses where cs-mucins are aberrantly expressed. 5 …”

“…All cs-mucin family members display large extracellular polypeptide structures supporting an array of branched and linear O-linked oligosaccharides that terminate in the sialic acid N-acetyl neuraminic acid (Neu5Ac). 5 The extracellular domain of the cs-mucin glycoprotein is non-covalently linked to a transmembrane domain and can be shed from the cell surface into the lumen or internalized by clathrin-mediated endocytosis for recycling. 6 These features enable cs-mucins to provide a barrier function to mucosal pathogens by displaying sites for pathogen binding, acting as a releasable decoy, and sterically blocking binding of pathogens to underlying cellular receptors.…”

Proteases and cystic fibrosis

“…Sputum biomarkers of IL-8, neutrophil counts, and neutrophil elastase correlate directly with disease severity (Mayer-Hamblett et al, 2007). Both bacterial exoproducts and neutrophil mediators upregulate production of mucin glycoproteins, the major macromolecular constituent of mucus (Rose and Voynow, 2006), and increase mucus secretion into the airway resulting in a favorable milieu for bacterial proliferation. Due to aberrant ion and water flux in the airway, mucus plaques become viscous which favors the development of biofilms (Matsui et al, 2006) and impedes neutrophil phagocytosis of bacteria (Matsui et al, 2005).…”

A Novel Role for IκB Kinase (IKK) α and IKKβ in ERK-Dependent Up-Regulation of MUC5AC Mucin Transcription by Streptococcus pneumoniae

“…Epithelial cells are not passive barriers, rather, they elaborate diverse molecules involved in efficient pathogen clearance. Mucins, the major constituent of mucus secretions, facilitate the mucociliary clearance by physically trapping inhaled microbial pathogens in the upper respiratory tract (2,3). Thus, up-regulation of mucins in infectious disease represents an important host innate defense response against invading microbes (3).…”