Caspase 8 inhibits programmed necrosis by processing CYLD
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/2348533
- author
- O'Donnell, Marie Anne ; Perez-Jimenez, Eva ; Oberst, Andrew ; Ng, Aylwin ; Massoumi, Ramin LU ; Xavier, Ramnik ; Green, Douglas R. and Ting, Adrian T.
- organization
- publishing date
- 2011
- 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
- pmid:22037414
- 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
- 2016-04-01 13:53:57
- date last changed
- 2022-05-07 19:46:21
@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}},
doi = {{10.1038/ncb2362}},
volume = {{13}},
year = {{2011}},
}