Munc18 isoforms play distinct roles in airway mucin secretion
Precise control of airway mucin secretion is essential for maintaining proper lung function. In this episode, Burton Dickey, Ana Jaramillo, and colleagues evaluate the role of different isoforms of the scaffolding protein Munc18 in the airway. Munc18a was required for baseline mucin secretion, Munc18b was linked to mucin secretion in response to stimuli, and Munc18c did not contribute to airway mucin secretion. Moreover, Munc18b-deficinet mice showed a reduction of pathogenic phenotypes in multiple models of airway disease, including allergic asthma, cystic fibrosis, and emphysema. These results highlight differences in exocytic machinery at baseline and in response to stimuli that have potential as therapeutic targets.
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Abstract
Airway mucin secretion is necessary for ciliary clearance of inhaled particles and pathogens but can be detrimental in pathologies such as asthma and cystic fibrosis. Exocytosis in mammals requires a Munc18 scaffolding protein, and airway secretory cells express all 3 Munc18 isoforms. Using conditional airway epithelial cell–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.
Authors
Ana M. Jaramillo, Lucia Piccotti, Walter V. Velasco, Anna Sofia Huerta Delgado, Zoulikha Azzegagh, Felicity Chung, Usman Nazeer, Junaid Farooq, Josh Brenner, Jan Parker-Thornburg, Brenton L. Scott, Christopher M. Evans, Roberto Adachi, Alan R. Burns, Silvia M. Kreda, Michael J. Tuvim, Burton F. Dickey
