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Acidic pH is essential for maintaining mast cell secretory granule homeostasis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..ORCID iD: 0000-0002-6779-391x
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2017 (English)In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 8, e2785Article in journal (Refereed) Published
Abstract [en]

It has been recognized for a long time that the secretory granules of mast cells are acidic, but the functional importance of maintaining an acidic pH in the mast cell granules is not fully understood. Here we addressed this issue by examining the effects of raising the pH of the mast cell secretory granules. Mast cells were incubated with bafilomycin A1, an inhibitor of the vacuolar-type ATPase proton pump. Supporting a role of vacuolar-type ATPase in mast cell granule acidification, bafilomycin A1 treatment caused a robust increase in granule pH. This was accompanied by marked effects on mast cell granules, including swelling and acquisition of vacuole-like morphology. Moreover, bafilomycin A1 caused extensive, yet selective effects on the granule content. These included aberrant processing of pro-carboxypeptidase A3 and a reduction in the level of intracellular histamine, the latter being accompanied by an increase in extracellular histamine. In contrast, the storage of beta-hexosaminidase, a prototype lysosomal hydrolase known to be stored in mast cell granules, was not affected by abrogation of granule acidification. Moreover, bafilomycin A1 caused a reduction of tryptase enzymatic activity and appearance of tryptase degradation products. Tryptase inhibition prevented the formation of such degradation products, suggesting that the pH elevation causes tryptase to undergo autoproteolysis. Taken together, our findings reveal that mast cell secretory granule homeostasis is critically dependent on an acidic milieu.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 8, e2785
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-326249DOI: 10.1038/cddis.2017.206ISI: 000402195700057PubMedID: 28492555OAI: oai:DiVA.org:uu-326249DiVA: diva2:1119467
Funder
Swedish Research CouncilSwedish Cancer SocietySwedish Heart Lung FoundationTorsten Söderbergs stiftelseMagnus Bergvall FoundationÅke Wiberg Foundation
Note

De tre första författarna delar förstaförfattarskapet.

Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2017-11-29Bibliographically approved

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