C70-35 Dominant Role of Vamp8 in Airway Mucin Secretion

Rationale

Airway mucus protects the lungs by trapping inhaled particles and pathogens, but dysregulated mucus secretion drives diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease. While mucin production and hydration have been studied extensively, the exocytic machinery controlling mucin secretion remains incompletely understood. Mucins are released at two rates: a low baseline rate and a high agonist-stimulated rate, which involve distinct scaffold protein paralogs (Munc18a for baseline and Munc18b for stimulated secretion).

Methods

We investigated the role of vesicle-associated membrane proteins (VAMPs), a family of SNARE proteins critical for exocytosis, in mediating these two modes of mucin secretion. Analysis of public single-cell RNA-seq datasets revealed that VAMP8 is the most abundantly expressed VAMP gene in human airway secretory cells. Using airway epithelium-specific VAMP8 deletant mice, we examined the requirement of VAMP8 for baseline and stimulated mucin secretion. Lung function was assessed in an Aspergillus Oryzae-induced allergic asthma model. To identify the VAMP isoform that predominantly mediates baseline secretion, we examined VAMP2 and VAMP3 due to their high expressions in secretory cells, including localization studies by immunofluorescence microscopy and functional testing using an inducible tetanus toxin-expressing mouse model.

Results

We found that VAMP8 is required for both baseline and stimulated mucin secretion. Lung function studies demonstrated reduced airway resistance in VAMP8 deletant mice in an Aspergillus Oryzae-induced allergic asthma model. Although VAMP2 is known to partner with Munc18a in neurons and localizes to mucin granules, combined deletion of VAMP2 and VAMP3 produced no detectable defect in baseline mucin secretion.

Conclusion

Together, these findings identify VAMP8 as a central mediator of both baseline and stimulated airway mucin secretion and reveal the unexpected complexity in the SNARE machinery governing baseline secretion.

This abstract is funded by: Cystic Fibrosis Foundation