Caspase 8 inhibits programmed necrosis by processing CYLD.
Caspase 8 inhibits programmed necrosis by processing CYLD.
复制标题
DOI：
10.1038/ncb2362
复制
发表时间：
2011-10-30
影响因子：
21.3
通讯作者：
中科院分区：
文献类型：
--
作者：
CASPASE 8通过自身切割和加工刽子手CASPASE 3，启动TNF死亡受体下游的细胞凋亡。然而，CASPASE 8的主要功能是传递促存活信号，抑制胚胎发生和造血过程中由RIPK1和RIPK3介导的程序性坏死（或坏死性坏死）。CASPASE 8抑制坏死细胞死亡需要它的催化活性，而不是凋亡所必需的自裂，然而，CASPASE 8处理的阻止坏死的关键底物一直是难以捉摸的。一个关键的底物必须满足三个标准：(1)它必须是程序性坏死所必需的；(2)在CASPASE 8阻断坏死的情况下，它必须被CASPASE 8切割；(3)底物上CASPASE 8加工位点的突变应该在不需要抑制CASPASE 8的情况下将促生存反应转化为坏死死亡。我们现在确定CYLD是满足这些标准的CASPASE 8的新型底物。在TNF刺激下，CASPASE 8切割CYLD产生存活信号。相反，CASPASE 8的缺失阻止了CYLD降解导致的坏死死亡。在对TNF的反应中，不能被CASPASE 8切割的D215上的CYLD替代突变将细胞存活转变为坏死细胞死亡。
CASPASE 8 initiates apoptosis downstream of TNF death receptors by undergoing autocleavage and processing the executioner CASPASE 3. 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 during embryogenesis and hematopoiesis. Suppression of necrotic cell death by CASPASE 8 requires its catalytic activity but not the autocleavage essential for apoptosis, however, the key substrate processed by CASPASE 8 to block necrosis has been elusive. A key substrate must meet three criteria: (1) it must be essential for programmed necrosis; (2) it must be cleaved by CASPASE 8 in situations where CASPASE 8 is blocking necrosis; and (3) 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 novel substrate for CASPASE 8 that satisfies these criteria. Upon 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 D215 that cannot be cleaved by CASPASE 8 switches cell survival to necrotic cell death in response to TNF.
登录
查看更多内容
影响因子：
64.8
作者：
Oberst, Andrew;Dillon, Christopher P.;Weinlich, Ricardo;McCormick, Laura L.;Fitzgerald, Patrick;Pop, Cristina;Hakem, Razq;Salvesen, Guy S.;Green, Douglas R.
通讯作者：
Green, Douglas R.
影响因子：
7.7
作者：
Friedman, Constantin S.;O'Donnell, Marie Anne;Ting, Adrian T.
通讯作者：
Ting, Adrian T.
影响因子：
12.4
作者：
Waring, P;Lambert, D;Beaver, J
通讯作者：
Beaver, J
影响因子：
16
作者：
Ea, CK;Deng, L;Chen, ZJJ
通讯作者：
Chen, ZJJ
影响因子：
11.8
作者：
Wright, Ato;Reiley, William W.;Sun, Shao-Cong
通讯作者：
Sun, Shao-Cong