Necrotic cell death in C. elegans requires the function of calreticulin and regulators of Ca(2+) release from the endoplasmic reticulum.
In C. elegans, a hyperactivated MEC-4(d) ion channel induces necrotic-like neuronal death that is distinct from apoptosis. We report that null mutations in calreticulin suppress both mec-4(d)-induced cell death and the necrotic cell death induced by expression of a constitutively activated Galpha(S) subunit. RNAi-mediated knockdown of calnexin, mutations in the ER Ca(2+) release channels unc-68 (ryanodine receptor) or itr-1 (inositol 1,4,5 triphosphate receptor), and pharmacological manipulations that block ER Ca(2+) release also suppress death. Conversely, thapsigargin-induced ER Ca(2+) release can restore mec-4(d)-induced cell death when calreticulin is absent. We conclude that high [Ca(2+)](i) is a requirement for necrosis in C. elegans and suggest that an essential step in the death mechanism is release of ER-based Ca(2+) stores. ER-driven Ca(2+) release has previously been implicated in mammalian necrosis, suggesting necrotic death mechanisms may be conserved.
Xu
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Department of Molecular Biology and Biochemistry, A232, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08855, USA.
Tavernarakis
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Driscoll
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D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins; D015220:Calcium Channels / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology*; D037281:Calnexin; D037282:Calreticulin; D048429:Cell Size; D002874:Chromosome Mapping; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015801:Helminth Proteins / Q000235:genetics / Q000502:physiology*; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D017136:Ion Transport / Q000187:drug effects; D007814:Larva; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D009336:Necrosis; D009410:Nerve Degeneration / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012261:Ribonucleoproteins / Q000235:genetics / Q000502:physiology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D019284:Thapsigargin / Q000494:pharmacology; D014110:Touch
D029742:Caenorhabditis elegans Proteins; D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D037282:Calreticulin; D015801:Helminth Proteins; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; C115871:Mec-4 protein, C elegans; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D012261:Ribonucleoproteins; D019837:Ryanodine Receptor Calcium Release Channel; C438601:Unc-68 protein, C elegans; D037281:Calnexin; D019284:Thapsigargin; D020962:Heterotrimeric GTP-Binding Proteins