Proteolytic histone modification by mast cell tryptase, a serglycin proteoglycan-dependent secretory granule protease.
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.
From the Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, 75123 Uppsala, Sweden.
Fabio R
FR
Melo
Francesca
F
Vita
Beata
B
Berent-Maoz
Francesca
F
Levi-Schaffer
Giuliano
G
Zabucchi
Gunnar
G
Pejler
D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D006657:Histones / Q000737:chemistry; D008407:Mast Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000737:chemistry* / Q000235:genetics; D022142:Secretory Vesicles / Q000378:metabolism*; D053802:Tryptases / Q000737:chemistry*; D033921:Vesicular Transport Proteins / Q000737:chemistry* / Q000235:genetics
D006657:Histones; D011509:Proteoglycans; D033921:Vesicular Transport Proteins; C075430:serglycin; D053802:Tryptases
Apoptosis; Histone Modification; Mast Cell; Protease; Proteoglycan; Proteolytic Enzymes; Secretory Granules; Serglycin; Tryptase; mMCP-6