Emerging cell and molecular targets for treating mucus hypersecretion in asthma

Abstract

Mucus provides a protective barrier that is crucial for host defense in the lungs. However, excessive or abnormal mucus can have pathophysiological consequences in many pulmonary diseases, including asthma. Patients with asthma are treated with agents that relax airway smooth muscle and reduce airway inflammation, but responses are often inadequate. In part, this is due to the inability of existing therapeutic agents to directly target mucus. Accordingly, there is a critical need to better understand how mucus hypersecretion and airway plugging are affected by the epithelial cells that synthesize, secrete, and transport mucus components. This review highlights recent advances in the biology of mucin glycoproteins with a specific focus on MUC5AC and MUC5B, the chief macromolecular components of airway mucus. An improved mechanistic understanding of key steps in mucin production and secretion will help reveal novel potential therapeutic strategies.

Keywords: Asthma; Mucin; Mucous cell; Mucus; Secretion.

Figure 1.

Mucin production and secretion have potential as targeting strategies to prevent or reverse effects of mucus hypersecretion. Key early steps include secretory epithelial cell lineage determining pathways, transcription regulators that affect MUC5AC and MUC5B expression, and regulatory mechanisms for additional biosynthesis or secretion-modulating components. As protein synthesis ensues, specialized transport, ER stress, chaperone, folding enzymes mediate formation of stabilized three-dimensional structures within the backbones of mucin proteins. In the ER C-terminal ends of mucin monomers dimerize through the formation of disulfide bonds that create stable cysteine-knot structures, and dimers are then transported to the Golgi apparatus. In the Golgi, glycosyltransferases first add GalNAc to serines and threonines along the PTS domains of mucin proteins. Further glycosylation forms core structures characterized by addition of Gal (yellow circles), GalNac (yellow squares), and/or GlcNAc (blue squares). Core glycans are then extended by addition of Gal and GlcNAc residues that can also harbor fucose (red triangles) or sulfate side chains (not shown). Mucin glycans are often terminated by the addition of sialic acid (purple diamonds) or fucose glycans to reducing ends of Gal moieties. Along with glycosylation, the Golgi is where mucin dimers form additional head-to-head disulfide bonds and thereby create even longer chains via their N-termini. Mature mucin glycopolymers are then packed into secretory granules where they are condensed and stored for subsequent secretion. This final step in this secretory pathway involves exocytic machinery components that drive secretory granule fusion with the plasma membrane and subsequent mucin release into airspaces where it forms mucus hydrogels. Biosynthesis, exocytosis, and post-secretory targets could be used to control muco-obstruction.