期刊
BIOCHEMICAL JOURNAL
卷 446, 期 -, 页码 383-394出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20120057
关键词
exocytosis; mast cell; mucin; mucus; Munc18; secretion
资金
- Cystic Fibrosis Foundation [08G0]
- National Institutes of Health [HL094848, HL097000, HL072984, CA16672, AI093533]
- MD Anderson Cancer Center
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 similar to 50%. Homozygous mutant mice were not viable, but heterozygotes showed a similar to 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 anaphylaxis was also reduced by similar to 50%, showing that reduction of Munc18b expression results in an attenuation of physiological responses dependent on MC degranulation. The Mune 18b 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 identify Munc18b as an essential gene that is a limiting component of the exocytic machinery of epithelial cells and MCs.
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