RaIB GTPase-mediated activation of the IκB family kinase TBK1 couples innate immune signaling to tumor cell survival
RaIB GTPase-mediated activation of the IκB family kinase TBK1 couples innate immune signaling to tumor cell survival
复制标题
DOI：
10.1016/j.cell.2006.08.034
复制
发表时间：
2006-10-06
期刊：
影响因子：
64.5
通讯作者：
White, Michael A.
中科院分区：
文献类型：
--
作者：
Chien, Yuchen;Kim, Sungchan;White, Michael A.
单体RaIGTPases、赖亚和RalB被认为是支持致瘤转化的调控框架的组分。具体而言，RaIB需要抑制凋亡检查点激活，其机制基础是未知的。报道的RaIB效应蛋白包括外囊的Sec 5组分，一种涉及囊泡与膜的束缚的八聚体蛋白复合物。令人惊讶的是，我们发现RaIB/Sec 5效应复合物直接募集并激活非典型I κ B激酶家族成员TBK 1。在癌细胞中，通过慢性RalB激活，该途径的组成性参与限制了通常在致癌应激背景下参与的凋亡程序的启动。虽然在非致瘤性环境中存活是必需的，但该途径有助于对病毒暴露产生先天免疫反应。这些观察结果定义了RaIGTPases对癌细胞存活的机制贡献，并揭示了RaIB/Sec 5效应复合物作为TBK 1依赖性先天免疫信号传导的组分。
The monomeric RaIGTPases, RaIA and RalB are recognized as components of a regulatory framework supporting tumorigenic transformation. Specifically, RaIB is required to suppress apoptotic checkpoint activation, the mechanistic basis of which is unknown. Reported effector proteins of RaIB include the Sec5 component of the exocyst, an octameric protein complex implicated in tethering of vesicles to membranes. Surprisingly, we find that the RaIB/Sec5 effector complex directly recruits and activates the atypical I kappa B kinase family member TBK1. In cancer cells, constitutive engagement of this pathway, via chronic RalB activation, restricts initiation of apoptotic programs typically engaged in the context of oncogenic stress. Although dispensable for survival in a nontumorigenic context, this pathway helps mount an innate immune response to virus exposure. These observations define the mechanistic contribution of RaIGTPases to cancer cell survival and reveal the RaIB/Sec5 effector complex as a component of TBK1-dependent innate immune signaling.