Serglycin Proteoglycan Promotes Apoptotic versus Necrotic Cell Death in Mast Cells

The mechanisms that govern whether a cell dies by apoptosis or necrosis are not fully understood. Here we show that serglycin, a secretory granule proteoglycan of hematopoietic cells, can have a major impact on this decision. Wild type and serglycin−/− mast cells were equally sensitive to a range of cell death-inducing regimens. However, whereas wild type mast cells underwent apoptotic cell death, serglycin−/− cells died predominantly by necrosis. Investigations of the underlying mechanism revealed that cell death was accompanied by leakage of secretory granule compounds into the cytosol and that the necrotic phenotype of serglycin−/− mast cells was linked to defective degradation of poly(ADP-ribose) polymerase-1. Cells lacking mouse mast cell protease 6, a major serglycin-associated protease, exhibited similar defects in apoptosis as observed in serglycin−/− cells, indicating that the pro-apoptotic function of serglycin is due to downstream effects of proteases that are complex-bound to serglycin. Together, these findings implicate serglycin in promoting apoptotic versus necrotic cell death. Serglycin is a secretory granule proteoglycan with a role in intracellular storage. In response to cell death-inducing agents, wild type mast cells die by apoptosis whereas serglycin−/− cells undergo necrosis. Serglycin promotes apoptotic versus necrotic cell death in mast cells. The present study implicates a pathway involving the secretory granule compartment in regulation of cell death.