Munc18b is an essential gene in mice whose expression is limiting for secretion by airway epithelial and mast cells.
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 anaphylaxis was 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 identify Munc18b as an essential gene that is a limiting component of the exocytic machinery of epithelial cells and MCs.
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Kyubo
K
Kim
Youlia M
YM
Petrova
Brenton L
BL
Scott
Rupesh
R
Nigam
Anurag
A
Agrawal
Christopher M
CM
Evans
Zoulikha
Z
Azzegagh
Alejandra
A
Gomez
Elsa M
EM
Rodarte
Vesa M
VM
Olkkonen
Rustam
R
Bagirzadeh
Lucia
L
Piccotti
Binhui
B
Ren
Joo-Heon
JH
Yoon
James A
JA
McNew
Roberto
R
Adachi
Michael J
MJ
Tuvim
Burton F
BF
Dickey
D000818:Animals; D004195:Disease Models, Animal; D024721:E-Box Elements; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D020043:Genes, Essential; D008168:Lung / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051938:Munc18 Proteins / Q000235:genetics* / Q000378:metabolism; D010323:Passive Cutaneous Anaphylaxis / Q000235:genetics; D051381:Rats
D051938:Munc18 Proteins