Molecular and Functional Identification of Two Mucin Secretory Pathways
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In airways, secreted mucins absorb large volumes of water to form viscoelastic mucus, which is then propelled proximally by ciliary beating and swallowed. Mucins are secreted both at a low baseline rate and a high agonist-stimulated rate; baseline secretion is primarily responsible for clearance of inhaled particles and pathogens, while stimulated secretion can induce airway obstruction protectively to trap helminths traversing the lungs or pathologically in asthma. Exocytosis requires a SNARE complex acting in concert with a Munc18 scaffolding protein. We previously found that Munc18b has the major scaffolding role in stimulated mucin secretion using heterozygous knockout mice. Here, we sought to identify the Munc18 protein mediating baseline secretion, and to test the hypothesis that selective impairment of stimulated secretion can protect against airway mucus obstruction. Using conditional airway epithelial deletant mice, we found that Munc18a has the major role in baseline mucin secretion, Munc18b has the major role in stimulated mucin secretion, and Munc18c does not function in mucin secretion. In an allergic asthma model, Munc18b deletion reduced airway mucus occlusion and airflow resistance. In a cystic fibrosis model, Munc18b deletion reduced airway mucus occlusion and emphysema. Munc18b deficiency in the airway epithelium did not result in any abnormalities of lung structure, particle clearance, inflammation, or bacterial infection. Our results show that regulated secretion in a polarized epithelial cell may involve more than one exocytic machine at the apical plasma membrane, and that the protective roles of mucin secretion can be preserved while therapeutically targeting its pathologic roles.
Jaramillo Hernandez, Ana Maria (2018). Molecular and Functional Identification of Two Mucin Secretory Pathways. Doctoral dissertation, Texas A & M University. Available electronically from