TMEM16A is indispensable for basal mucus secretion in airways and intestine

What is it about?

Mucus in airways and intestine represents an innate defense against pathogens. Mucus traps inhaled pathogens and particles, physically separates bacteria from epithelial cells and lubricates the intestinal content. Proper airway mucociliary clearance and intestinal mucosal immunity is due to specialized cells, which produce and secrete mucus. Mucus is produced and secreted continuously at a basal level (constitutive secretion), or upon acute stimulation with agonists such as acetylcholine. How these specialized cells produce and secrete mucus is only partially understood. It has been shown that the Ca2+ activated Cl- channel TMEM16A is strongly upregulated during lung/airway diseases that produce large quantities of mucus, such as cystic fibrosis, chronic obstructive lung disease caused by cigarette smoking, and asthma. However, the role of this Cl- channel upregulated in mucus producing cells is unclear. The present data demonstrate for the first time that TMEM16A controls cellular exocytosis. We also show that TMEM16A is indispensable for basal and ATP-driven mucus release by airway club (Clara) cells. This is also the first report that demonstrates a novel mechanism for ATP-driven mucus release by intestinal goblet cells. TMEM16A controls spatial intracellular calcium levels required for fusion of mucus containing granules with the apical membrane. The results provide the basis for a novel therapeutic approach for the treatment of inflammatory airway diseases accompanied by mucus hypersecretion.

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