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Ctr2 Regulates Mast Cell Maturation by Affecting the Storage and Expression of Tryptase and Proteoglycans
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA..
Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2015 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 195, no 8, 3654-3664 p.Article in journal (Refereed) Published
Abstract [en]

Copper (Cu) is essential for multiple cellular functions. Cellular uptake of Cu+ is carried out by the Ctr1 high-affinity Cu transporter. The mobilization of endosomal Cu pools is regulated by a protein structurally similar to Ctr1, called Ctr2. It was recently shown that ablation of Ctr2 caused an increase in the concentration of Cu localized to endolysosomes. However, the biological significance of excess endolysosomal Cu accumulation has not been assessed. In this study, we addressed this issue by investigating the impact of Ctr2 deficiency on mast cells, a cell type unusually rich in endolysosomal organelles (secretory granules). We show that Ctr2(-/-) mast cells have increased intracellular Cu concentrations and that the absence of Ctr2 results in increased metachromatic staining, the latter indicating an impact of Ctr2 on the storage of proteoglycans in the secretory granules. In agreement with this, the absence of Ctr2 caused a skewed ratio between proteoglycans of heparin and chondroitin sulfate type, with increased amounts of heparin accompanied by a reduction of chondroitin sulfate. Moreover, transmission electron microscopy analysis revealed a higher number of electron-dense granules in Ctr2(-/-) mast cells than in wild-type cells. The increase in granular staining and heparin content is compatible with an impact of Ctr2 on mast cell maturation and, in support of this, the absence of Ctr2 resulted in markedly increased mRNA expression, storage, and enzymatic activity of tryptase. Taken together, the present study introduces Ctr2 and Cu as novel actors in the regulation of mast cell maturation and granule homeostasis.

Place, publisher, year, edition, pages
2015. Vol. 195, no 8, 3654-3664 p.
National Category
Immunology in the medical area
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URN: urn:nbn:se:uu:diva-266701DOI: 10.4049/jimmunol.1500283ISI: 000362968100020PubMedID: 26342034OAI: oai:DiVA.org:uu-266701DiVA: diva2:868808
Funder
Swedish Research Council, 524-2014-1, 521-2013-3870Swedish Cancer SocietySwedish Heart Lung FoundationSwedish Research Council FormasNIH (National Institute of Health), DK074192
Available from: 2015-11-11 Created: 2015-11-10 Last updated: 2017-12-01Bibliographically approved

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Öhrvik, HelenaEriksson, IngerKjellen, LenaPejler, Gunnar

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