An intracellular serpin regulates necrosis by inhibiting the induction and sequelae of lysosomal injury.
Extracellular serpins such as antithrombin and alpha1-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.
Luke
Cliff J
CJ
UPMC Newborn Medicine Program, Departments of Pediatrics Children's Hospital of Pittsburgh and Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA 15213, USA.
Pak
Stephen C
SC
Askew
Yuko S
YS
Naviglia
Terra L
TL
Askew
David J
DJ
Nobar
Shila M
SM
Vetica
Anne C
AC
Long
Olivia S
OS
Watkins
Simon C
SC
Stolz
Donna B
DB
Barstead
Robert J
RJ
Moulder
Gary L
GL
Brömme
Dieter
D
Silverman
Gary A
GA
D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D048429:Cell Size; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006358:Hot Temperature; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation; D009336:Necrosis; D009997:Osmotic Pressure; D018384:Oxidative Stress; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D029742:Caenorhabditis elegans Proteins; D015220:Calcium Channels; D034741:RNA, Small Interfering; D015843:Serpins; C523762:srp-6 protein, C elegans; D002154:Calpain; D003546:Cysteine Endopeptidases; D002118:Calcium