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Caspase 8 inhibits programmed necrosis by processing CYLD.

Caspase 8 initiates apoptosis downstream of TNF death receptors by undergoing autocleavage and processing the executioner caspase 3 (ref. 1). However, the dominant function of caspase 8 is to transmit a pro-survival signal that suppresses programmed necrosis (or necroptosis) mediated by RIPK1 and RIPK3 (refs 2-6) during embryogenesis and haematopoiesis(7-9). Suppression of necrotic cell death by caspase 8 requires its catalytic activity but not the autocleavage essential for apoptosis(10); however, the key substrate processed by caspase 8 to block necrosis has been elusive. A key substrate must meet three criteria: it must be essential for programmed necrosis; it must be cleaved by caspase 8 in situations where caspase 8 is blocking necrosis; and mutation of the caspase 8 processing site on the substrate should convert a pro-survival response to necrotic death without the need for caspase 8 inhibition. We now identify CYLD as a substrate for caspase 8 that satisfies these criteria. Following TNF stimulation, caspase 8 cleaves CYLD to generate a survival signal. In contrast, loss of caspase 8 prevented CYLD degradation, resulting in necrotic death. A CYLD substitution mutation at Asp 215 that cannot be cleaved by caspase 8 switches cell survival to necrotic cell death in response to TNF.

Pubmed ID: 22037414

Authors

  • O'Donnell MA
  • Perez-Jimenez E
  • Oberst A
  • Ng A
  • Massoumi R
  • Xavier R
  • Green DR
  • Ting AT

Journal

Nature cell biology

Publication Data

December 2, 2011

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI052417
  • Agency: NIAID NIH HHS, Id: AI44828
  • Agency: NIDDK NIH HHS, Id: P30 DK043351
  • Agency: NIAID NIH HHS, Id: R01 AI044828
  • Agency: NIAID NIH HHS, Id: R01 AI044828-13
  • Agency: NIAID NIH HHS, Id: R01 AI052417
  • Agency: NIGMS NIH HHS, Id: R01 GM052735
  • Agency: NIGMS NIH HHS, Id: R01 GM052735-11

Mesh Terms

  • Animals
  • Caspase 8
  • Cell Survival
  • Cells, Cultured
  • Embryo, Mammalian
  • Female
  • Fibroblasts
  • HEK293 Cells
  • Humans
  • Jurkat Cells
  • Mice
  • Necrosis
  • Protein Processing, Post-Translational
  • Signal Transduction
  • Tumor Suppressor Proteins