An Intracellular Serpin Regulates Necrosis by Inhibiting the Induction and Sequelae of Lysosomal Injury

Extracellular serpins such as antithrombin and α1-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 b...

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Bibliographic Details
Published in:Cell 2007-09, Vol.130 (6), p.1108-1119
Main Authors: Luke, Cliff J., Pak, Stephen C., Askew, Yuko S., Naviglia, Terra L., Askew, David J., Nobar, Shila M., Vetica, Anne C., Long, Olivia S., Watkins, Simon C., Stolz, Donna B., Barstead, Robert J., Moulder, Gary L., Brömme, Dieter, Silverman, Gary A.
Format: Article
Language:English
Subjects:
Animals
Caenorhabditis elegans - enzymology
Caenorhabditis elegans - genetics
Caenorhabditis elegans - metabolism
Caenorhabditis elegans - ultrastructure
Caenorhabditis elegans Proteins - genetics
Caenorhabditis elegans Proteins - metabolism
Calcium - metabolism
Calcium Channels - metabolism
Calpain - genetics
Calpain - metabolism
Cell Hypoxia
Cell Size
CELLBIO
Cysteine Endopeptidases - genetics
Cysteine Endopeptidases - metabolism
Genotype
Hot Temperature
Lysosomes - enzymology
Lysosomes - metabolism
Lysosomes - ultrastructure
Mutation
Necrosis
Osmotic Pressure
Oxidative Stress
Phenotype
PROTEINS
RNA Interference
RNA, Small Interfering - metabolism
Serpins - genetics
Serpins - metabolism
Time Factors
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Summary:Extracellular serpins such as antithrombin and α1-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.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2007.07.013