Proteolytic Histone Modification by Mast Cell Tryptase, a Serglycin Proteoglycan-dependent Secretory Granule Protease
2014 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 289, no 11, 7682-7690 p.Article in journal (Refereed) Published
Background: Tryptase is a serglycin proteoglycan-dependent protease localized in mast cell granules. Results: Tryptase was found to degrade core histones, both during apoptosis and in viable cells. Conclusion: A serglycin-tryptase axis is identified as a novel mechanism for histone modification. Significance: Secretory granule compounds are implicated in the regulation of nuclear events. A hallmark feature of mast cells is their high content of cytoplasmic secretory granules filled with various preformed compounds, including proteases of tryptase-, chymase-, and carboxypeptidase A3 type that are electrostatically bound to serglycin proteoglycan. Apart from participating in extracellular processes, serglycin proteoglycan and one of its associated proteases, tryptase, are known to regulate cell death by promoting apoptosis over necrosis. Here we sought to outline the underlying mechanism and identify core histones as primary proteolytic targets for the serglycin-tryptase axis. During the cell death process, tryptase was found to relocalize from granules into the cytosol and nucleus, and it was found that the absence of tryptase was associated with a pronounced accumulation of core histones both in the cytosol and in the nucleus. Intriguingly, tryptase deficiency resulted in defective proteolytic modification of core histones even at baseline conditions, i.e. in the absence of cytotoxic agent, suggesting that tryptase has a homeostatic impact on nuclear events. Indeed, tryptase was found in the nucleus of viable cells and was shown to cleave core histones in their N-terminal tail. Moreover, it was shown that the absence of the serglycin-tryptase axis resulted in altered chromatin composition. Together, these findings implicate histone proteolysis through a secretory granule-derived serglycin-tryptase axis as a novel principle for histone modification, during both cell homeostasis and cell death.
Place, publisher, year, edition, pages
2014. Vol. 289, no 11, 7682-7690 p.
Apoptosis, Histone Modification, Mast Cell, Protease, Proteoglycan, Proteolytic Enzymes, mMCP-6, Secretory Granules, Serglycin, Tryptase
Cancer and Oncology
IdentifiersURN: urn:nbn:se:uu:diva-316863DOI: 10.1074/jbc.M113.546895ISI: 000332761500036PubMedID: 24478313OAI: oai:DiVA.org:uu-316863DiVA: diva2:1079167
FunderSwedish Research CouncilSwedish Cancer Society