A role for serglycin proteoglycan in mast cell apoptosis induced by a secretory granule-mediated pathway.
Mast cell secretory granules (secretory lysosomes) contain large amounts of fully active proteases bound to serglycin proteoglycan. Damage to the granule membrane will thus lead to the release of serglycin and serglycin-bound proteases into the cytosol, which potentially could lead to proteolytic activation of cytosolic pro-apoptotic compounds. We therefore hypothesized that mast cells are susceptible to apoptosis induced by permeabilization of the granule membrane and that this process is serglycin-dependent. Indeed, we show that wild-type mast cells are highly sensitive to apoptosis induced by granule permeabilization, whereas serglycin-deficient cells are largely resistant. The reduced sensitivity of serglycin(-/-) cells to apoptosis was accompanied by reduced granule damage, reduced release of proteases into the cytosol, and defective caspase-3 activation. Mechanistically, the apoptosis-promoting effect of serglycin involved serglycin-dependent proteases, as indicated by reduced sensitivity to apoptosis and reduced caspase-3 activation in cells lacking individual mast cell-specific proteases. Together, these findings implicate serglycin proteoglycan as a novel player in mast cell apoptosis.
Department of Anatomy, Physiology, and Biochemistry, Swedish University of Agricultural Sciences, SE-75123 Uppsala, Sweden.
Fabio Rabelo
FR
Melo
Ida
I
Waern
Elin
E
Rönnberg
Magnus
M
Åbrink
David M
DM
Lee
Susan M
SM
Schlenner
Thorsten B
TB
Feyerabend
Hans-Reimer
HR
Rodewald
Boris
B
Turk
Sara
S
Wernersson
Gunnar
G
Pejler
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D007425:Intracellular Membranes / Q000378:metabolism*; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D022142:Secretory Vesicles / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
D011509:Proteoglycans; D033921:Vesicular Transport Proteins; C075430:serglycin; C505409:Casp3 protein, mouse; D053148:Caspase 3