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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

Martin, Sebastin Santosh; Melo, Fabio Rabelo; Pejler, Gunnar

Sammanfattning

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.

Nyckelord

mast cells; tryptase; cell stress; Psme4; glutathione; thioredoxin

Publicerad i

Cells
2019, Volym: 8, nummer: 10, artikelnummer: 1190
Utgivare: MDPI

    UKÄ forskningsämne

    Cell- och molekylärbiologi

    Publikationens identifierare

    DOI: https://doi.org/10.3390/cells8101190

    Permanent länk till denna sida (URI)

    https://res.slu.se/id/publ/102886