MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival
MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival
复制标题
DOI：
10.1084/jem.20070868
复制
发表时间：
2007-09-03
影响因子：
15.3
通讯作者：
Ding, Aihao
中科院分区：
文献类型：
--
作者：
Kim, Younghwa;Zhou, Ping;Ding, Aihao
天然免疫系统依赖于进化上保守的Toll样受体(TLRs)来识别不同的微生物分子结构。大多数TLR依赖于被称为MyD88s的适配器蛋白家族来转导它们的信号。MyD88-1-4在宿主防御中的关键作用被基因敲除小鼠的免疫反应缺陷所证明。相比之下，脊椎动物MyD88-5的表达部位和功能仍然难以捉摸。我们发现MyD88-5与其他MyD88的不同之处在于，MyD88-5优先在神经元中表达，部分与线粒体和JNK3共定位，并调控神经元死亡。我们通过细菌人工染色体制备了MyD88-5/GFP转基因小鼠，以保持其内源性表达模式。MyD88-5/GFP主要在脑中检测到，它与神经元内的点状结构相关，并与部分线粒体结合。在体外，MyD88-5与JNK3共沉淀，并将JNK3从胞浆募集到线粒体。MyD88-5基因缺陷小鼠的海马神经元在缺氧和葡萄糖剥夺后免于死亡。相比之下，MyD88-5缺失的巨噬细胞对微生物产物的反应就像野生型细胞一样。因此，在介导应激诱导的神经元毒性方面，MyD88-5似乎是MyD88中独一无二的。
The innate immune system relies on evolutionally conserved Toll-like receptors ( TLRs) to recognize diverse microbial molecular structures. Most TLRs depend on a family of adaptor proteins termed MyD88s to transduce their signals. Critical roles of MyD88-1-4 in host defense were demonstrated by defective immune responses in knockout mice. In contrast, the sites of expression and functions of vertebrate MyD88-5 have remained elusive. We show that MyD88-5 is distinct from other MyD88s in that MyD88-5 is preferentially expressed in neurons, colocalizes in part with mitochondria and JNK3, and regulates neuronal death. We prepared MyD88-5/ GFP transgenic mice via a bacterial artificial chromosome to preserve its endogenous expression pattern. MyD88-5/ GFP was detected chiefly in the brain, where it associated with punctate structures within neurons and copurified in part with mitochondria. In vitro, MyD88-5 coimmunoprecipitated with JNK3 and recruited JNK3 from cytosol to mitochondria. Hippocampal neurons from MyD88-5-deficient mice were protected from death after deprivation of oxygen and glucose. In contrast, MyD88-5 null macrophages behaved like wild-type cells in their response to microbial products. Thus, MyD88-5 appears unique among MyD88s in functioning to mediate stress-induced neuronal toxicity.