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

Cell. 2007 Sep 21;130(6):1108-19. doi: 10.1016/j.cell.2007.07.013.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism
  • Genotype
  • Hot Temperature
  • Lysosomes / enzymology
  • Lysosomes / metabolism*
  • Lysosomes / ultrastructure
  • Mutation
  • Necrosis
  • Osmotic Pressure
  • Oxidative Stress
  • Phenotype
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Serpins / genetics
  • Serpins / metabolism*
  • Time Factors

Substances

  • Caenorhabditis elegans Proteins
  • Calcium Channels
  • RNA, Small Interfering
  • Serpins
  • srp-6 protein, C elegans
  • Calpain
  • Cysteine Endopeptidases
  • Calcium