An intracellular serpin regulates necrosis by inhibiting the induction and sequelae of lysosomal injury

Extracellular serpins such as antithrombin and a1- antitrypsin are the quintessential regulators of proteolytic pathways. In contrast, the biological functions of the intracellular serpins remain obscure. We now report that the C. elegans intracellular serpin, SRP- 6, exhibits a prosurvival function by blocking necrosis. Minutes after hypotonic shock, srp- 6 null animals underwent a catastrophic series of events culminating in lysosomal disruption, cytoplasmic proteolysis, and death. This newly defined hypo- osmotic stress lethal ( Osl) phenotype was dependent upon calpains and lysosomal cysteine peptidases, two in vitro targets of SRP- 6. By protecting against both the induction of and the lethal effects from lysosomal injury, SRP- 6 also blocked death induced by heat shock, oxidative stress, hypoxia, and cation channel hyperactivity. These findings suggest that multiple noxious stimuli converge upon a peptidase- driven, core stress response pathway that, in the absence of serpin regulation, triggers a lysosomal- dependent necrotic cell death routine.