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Caspase 8 inhibits programmed necrosis by processing CYLD

O'Donnell, Marie Anne; Perez-Jimenez, Eva; Oberst, Andrew; Ng, Aylwin; Massoumi, Ramin LU ; Xavier, Ramnik; Green, Douglas R. and Ting, Adrian T. (2011) In Nature Cell Biology 13(12). p.132-1437
Abstract
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... (More)
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. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Nature Cell Biology
volume
13
issue
12
pages
132 - 1437
publisher
Nature Publishing Group
external identifiers
  • wos:000298157500011
  • scopus:84856160569
ISSN
1465-7392
DOI
10.1038/ncb2362
language
English
LU publication?
yes
id
fe5fa856-288d-4a97-9f74-5108a702391a (old id 2348533)
date added to LUP
2012-03-01 11:25:47
date last changed
2017-11-05 04:03:26
@article{fe5fa856-288d-4a97-9f74-5108a702391a,
  abstract     = {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.},
  author       = {O'Donnell, Marie Anne and Perez-Jimenez, Eva and Oberst, Andrew and Ng, Aylwin and Massoumi, Ramin and Xavier, Ramnik and Green, Douglas R. and Ting, Adrian T.},
  issn         = {1465-7392},
  language     = {eng},
  number       = {12},
  pages        = {132--1437},
  publisher    = {Nature Publishing Group},
  series       = {Nature Cell Biology},
  title        = {Caspase 8 inhibits programmed necrosis by processing CYLD},
  url          = {http://dx.doi.org/10.1038/ncb2362},
  volume       = {13},
  year         = {2011},
}