Munc18b is an essential gene in mice whose expression is limiting for secretion by airway epithelial and mast cells

Kyubo Kim, Youlia M. Petrova, Brenton L. Scott, Rupesh Nigam, Anurag Agrawal, Christopher M. Evans, Zoulikha Azzegagh, Alejandra Gomez, Elsa M. Rodarte, Vesa M. Olkkonen, Rustam Bagirzadeh, Lucia Piccotti, Binhui Ren, Joo Heon Yoon, James A. McNew, Roberto Adachi, Michael J. Tuvim, Burton F. Dickey

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Airway mucin secretion and MC (mast cell) degranulation must be tightly controlled for homoeostasis of the lungs and immune system respectively. We found the exocytic protein Munc18b to be highly expressed in mouse airway epithelial cells and MCs, and localized to the apical pole of airway secretory cells. To address its functions, we created a mouse with a severely hypomorphic Munc18b allele such that protein expression in heterozygotes was reduced by ∼ 50%. Homozygous mutant mice were not viable, but heterozygotes showed a ∼ 50% reduction in stimulated release of mucin from epithelial cells and granule contents from MCs. The defect in MCs affected only regulated secretion and not constitutive or transporter-mediated secretion. The severity of passive cutaneous anaphylaxiswas also reduced by ∼ 50%, showing that reduction of Munc18b expression results in an attenuation of physiological responses dependent on MC degranulation. The Munc18b promoter is controlled by INR (initiator), Sp1 (specificity protein 1), Ets, CRE (cAMP-response element), GRE (glucocorticoid-response element), GATA and E-box elements in airway epithelial cells; however, protein levels did not change during mucous metaplasia induced by allergic inflammation. Taken together, the results of the present study identifyMunc18b as an essential gene that is a limiting component of the exocytic machinery of epithelial cells and MCs.

Original languageEnglish (US)
Pages (from-to)383-394
Number of pages12
JournalBiochemical Journal
Volume446
Issue number3
DOIs
StatePublished - Sep 15 2012

Keywords

  • Exocytosis
  • Mast cell
  • Mucin
  • Mucus
  • Munc18
  • Secretion

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

MD Anderson CCSG core facilities

  • Flow Cytometry and Cellular Imaging Facility
  • Genetically Engineered Mouse Facility
  • Research Animal Support Facility

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