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The Absence of Tryptase Mcpt6 Causes Elevated Cellular Stress in Response to Modulation of the Histone Acetylation Status in Mast Cells
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. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, S-75007 Uppsala, Sweden.ORCID iD: 0000-0002-6779-391x
2019 (English)In: CELLS, ISSN 2073-4409, Vol. 8, no 10, article id 1190Article in journal (Refereed) Published
Abstract [en]

Mast cells contain large amounts of proteases stored within their secretory granules. Previously we showed that one of these proteases, tryptase, in addition to its location within granules, can also be found within the mast cell nucleus, where it has the capacity to affect the acetylation profile of nucleosomal core histones in aging cells. Based on this notion, and on the known sensitivity of mast cells to modulation of histone acetylation, we here asked whether tryptase could impact on the responses against cellular stress caused by disturbed histone acetylation status. To address this, wild-type and tryptase-deficient (Mcpt6(-/-)) mast cells were subjected to cell stress caused by trichostatin A (TSA), a histone deacetylase inhibitor. Wild-type and Mcpt6(-/-) mast cells were equally sensitive to TSA at an early stage of culture (similar to 8 weeks). However, in aging mast cells (>50 weeks), tryptase-deficiency led to increased sensitivity to cell death. To address the underlying mechanism, we assessed effects of tryptase deficiency on the expression of markers for proliferation and cell stress. These analyses revealed aberrant regulation of thioredoxin, thioredoxin reductase, glutaredoxin, and glutathione reductase, as well as blunted upregulation of ribonucleotide reductase subunit R2 in response to TSA in aging cells. Moreover, the absence of tryptase led to increased expression of Psme4/PA200, a proteasome variant involved in the processing of acetylated core histones. Altogether, this study identifies a novel role for tryptase in regulating the manifestations of cell stress in aging mast cells.

Place, publisher, year, edition, pages
2019. Vol. 8, no 10, article id 1190
Keywords [en]
mast cells, tryptase, cell stress, Psme4, glutathione, thioredoxin
National Category
Immunology
Identifiers
URN: urn:nbn:se:uu:diva-397955DOI: 10.3390/cells8101190ISI: 000497336400079PubMedID: 31581668OAI: oai:DiVA.org:uu-397955DiVA, id: diva2:1382224
Funder
Swedish Research CouncilSwedish Cancer SocietySwedish Heart Lung FoundationSwedish Childhood Cancer FoundationKnut and Alice Wallenberg FoundationAvailable from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-01-02Bibliographically approved

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