Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation.
Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation.
复制标题
DOI：
10.1016/j.cell.2009.05.037
复制
发表时间：
2009-06-12
期刊：
影响因子：
64.5
通讯作者：
Chan FK
中科院分区：
文献类型：
--
作者：
Cho YS;Challa S;Moquin D;Genga R;Ray TD;Guildford M;Chan FK
程序性坏死是一种不依赖半胱天冬酶的细胞死亡，其分子调控机制尚不清楚。蛋白激酶RIP 1对程序性坏死至关重要。由于RIP 1也介导促存活转录因子NF-κB的激活，我们推测需要额外的分子来特异性激活程序性坏死。使用RNA干扰筛选，我们确定了RIP 3作为一个关键的激活程序性坏死诱导的TNF和病毒感染。RIP 3调节坏死特异性RIP 1磷酸化。RIP 1和RIP 3的磷酸化稳定了它们在促坏死复合物中的结合，激活促坏死激酶活性，并触发下游活性氧簇的产生。在牛痘病毒感染期间诱导促坏死RIP 1-RIP 3复合物。因此，RIP 3 −/−小鼠表现出严重受损的病毒诱导的组织坏死，炎症和病毒复制的控制。因此，RIP 3通过启动促坏死激酶级联来控制程序性坏死，该促坏死激酶级联对于针对病毒感染的先天性炎症反应是必需的。
Programmed necrosis is a form of caspase-independent cell death whose molecular regulation is poorly understood. The protein kinase RIP1 is crucial for programmed necrosis. Because RIP1 also mediates activation of the pro-survival transcription factor NF-κB, we postulated that additional molecules are required to specifically activate programmed necrosis. Using a RNA interference screen, we identified RIP3 as a crucial activator for programmed necrosis induced by TNF and during virus infection. RIP3 regulates necrosis-specific RIP1 phosphorylation. The phosphorylation of RIP1 and RIP3 stabilizes their association within the pro-necrotic complex, activates the pro-necrotic kinase activity, and triggers downstream reactive oxygen species production. The pro-necrotic RIP1-RIP3 complex is induced during vaccinia virus infection. Consequently, RIP3−/− mice exhibited severely impaired virus-induced tissue necrosis, inflammation, and control of viral replication. Thus, RIP3 controls programmed necrosis by initiating the pro-necrotic kinase cascade that is essential for the innate inflammatory response against virus infections.
登录
查看更多内容
影响因子：
16
作者：
Kim, You-Sun;Morgan, Michael J.;Liu, Zheng-Gang
通讯作者：
Liu, Zheng-Gang
影响因子：
64.5
作者：
Micheau, O;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
30.5
作者：
Cauwels, A;Janssen, B;Brouckaert, P
通讯作者：
Brouckaert, P
影响因子：
10.5
作者：
Lin, Y;Devin, A;Liu, ZG
通讯作者：
Liu, ZG
影响因子：
4.8
作者：
Lewis, J;Devin, A;Liu, ZG
通讯作者：
Liu, ZG