Munc13-2-/- baseline secretion defect reveals source of oligomeric mucins in mouse airways.
Since the airways of control mouse lungs contain few alcian blue/periodic acid-Schiff's (AB/PAS)+ staining 'goblet' cells in the absence of an inflammatory stimulus such as allergen sensitization, it was surprising to find that the lungs of mice deficient for the exocytic priming protein Munc13-2 stain prominently with AB/PAS under control conditions. Purinergic agonists (ATP/UTP) stimulated release of accumulated mucins in the Munc13-2-deficient airways, suggesting that the other airway isoform, Munc13-4, supports agonist-regulated secretion. Notably, however, not all of the mucins in Munc13-2-deficient airways were secreted, suggesting a strict Munc13-2 priming requirement for a population of secretory granules. AB/PAS+ staining of Munc13-2-deficient airways was not caused by an inflammatory, metaplastic-like response: bronchial-alveolar lavage leucocyte numbers, Muc5ac and Muc5b mRNA levels, and Clara cell ultrastructure (except for increased secretory granule numbers) were all normal. A Muc5b-specific antibody indicated the presence of this mucin in Clara cells of wildtype (WT) control mice, and increased amounts in Munc13-2-deficient mice. Munc13-2 therefore appears to prime a regulated, baseline secretory pathway, such that Clara cell Muc5b, normally secreted soon after synthesis, accumulates in the gene-deficient animals, making them stain AB/PAS+. The defective priming phenotype is widespread, as goblet cells of several mucosal tissues appear engorged and Clara cells accumulated Clara cell secretory protein (CCSP) in Munc13-2-deficient mice. Additionally, because in the human airways, MUC5AC localizes to the surface epithelium and MUC5B to submucosal glands, the finding that Muc5b is secreted by Clara cells under control conditions may indicate that it is also secreted tonically from human bronchiolar Clara cells.
Zhu
Yunxiang
Y
Cystic Fibrosis/Pulmonary Research & Treatment Center, University of North Carolina, Chapel Hill, NC 27599-7248, USA.
Ehre
Camille
C
Abdullah
Lubna H
LH
Sheehan
John K
JK
Roy
Michelle
M
Evans
Christopher M
CM
Dickey
Burton F
BF
Davis
C William
CW
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055271:Mucin 5AC; D055257:Mucin-5B; D009077:Mucins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012137:Respiratory System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014132:Trachea / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014544:Uridine Triphosphate / Q000494:pharmacology; D014598:Uteroglobin / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; C524678:MUC5AC protein, human; C524578:MUC5B protein, human; D008565:Membrane Proteins; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D055257:Mucin-5B; D009077:Mucins; D009419:Nerve Tissue Proteins; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse; C485549:Unc13b protein, mouse; C520225:Unc13d protein, mouse; D000255:Adenosine Triphosphate; D014598:Uteroglobin; D014544:Uridine Triphosphate