Regulated mucin secretion from airway epithelial cells

Area of Science:

• Cell Biology
• Respiratory System Physiology
• Molecular Mechanisms of Secretion

Background:

• Airway epithelial cells synthesize and secrete gel-forming polymeric mucins, crucial for mucus barrier function.
• Mucus, formed by mucins and water, removes inhaled pathogens and particles via ciliary action.
• The intracellular trafficking and regulated exocytosis of mucins present unique cell biology challenges due to their large size.

Purpose of the Study:

• To investigate the cell biology of regulated exocytosis in airway secretory cells, focusing on mucin trafficking and secretion.
• To compare the mucin exocytosis pathway with those in neuroendocrine cells and neurons.
• To identify key molecular players and signaling pathways involved in basal and stimulated mucin secretion.

Main Methods:

• Analysis of mucin polymerization, O-glycosylation, and storage in secretory granules.
• Investigation of the role of specific proteins (e.g., Agr2, Munc13-2, Synaptotagmin-2, SNARE proteins) in mucin trafficking and exocytosis.
• Examination of signaling pathways involving purinergic and adenosine receptors, Gq-coupled phospholipase C, calcium, and diacylglycerol (DAG).

Main Results:

• Polymeric mucins undergo extensive polymerization and glycosylation in the ER and Golgi, with sugar chains comprising >70% of their mass.
• Mature mucins are stored in large granules, translocated to the apical membrane via interactions with cytoskeletal and scaffolding proteins.
• Both basal and stimulated mucin secretion are regulated exocytic events, dependent on Munc13-2, calcium, and DAG, with distinct sensors for each rate.

Conclusions:

• The airway secretory cell provides a model system for studying regulated exocytosis of large, complex molecules.
• The core exocytic machinery involves VAMP8, SNAP23, an unknown Syntaxin, and Munc18b, with similarities and differences to neuronal and neuroendocrine secretion.
• Understanding mucin secretion is vital for respiratory health and disease, highlighting the importance of these cellular mechanisms.