Alix, making a link between apoptosis-linked gene-2, the endosomal sorting complexes required for transport, and neuronal death in vivo
Alix, making a link between apoptosis-linked gene-2, the endosomal sorting complexes required for transport, and neuronal death in vivo
复制标题
DOI：
10.1523/jneurosci.3069-05.2006
复制
发表时间：
2006-01-11
影响因子：
5.3
通讯作者：
Sadoul, R
中科院分区：
文献类型：
--
作者：
Mahul-Mellier, AL;Hemming, FJ;Sadoul, R
阿利克斯/阿尔茨海默病连锁基因-2（ALG-2）相互作用蛋白X是一种衔接蛋白，通过结合内亲蛋白和转运所需的内体分选复合物（ESCRT）蛋白TSG 101和CHMP 4 b参与内溶酶体系统的调节。它首先被表征为ALG-2的相互作用物，ALG-2是细胞死亡所必需的钙结合蛋白，并且一些观察结果表明阿利克斯在控制细胞死亡中的作用。我们在鸡胚中使用电穿孔来测试过表达的野生型或突变的阿利克斯蛋白是否影响体内细胞死亡。我们发现，阿利克斯过表达足以诱导神经上皮细胞的细胞死亡。这种作用严格依赖于其与ALG-2结合的能力。另一方面，缺乏ALG-2或CHMP 4 b结合位点的阿利克斯突变体的表达防止了鸡胚发育第4.5天颈部运动神经元中的早期程序性细胞死亡。这种由阿利克斯突变体提供的保护作用在TSG 101结合位点缺失后被消除，而不是在亲内蛋白结合位点缺失后被消除。我们的研究结果表明，ALG-2/阿利克斯复合物与ESCRT蛋白的相互作用是必要的自然发生的运动神经元死亡。因此，阿利克斯代表了内溶酶体系统和细胞死亡机制之间的分子联系。
Alix/apoptosis-linked gene-2 (ALG-2)-interacting protein X is an adaptor protein involved in the regulation of the endolysosomal system through binding to endophilins and to endosomal sorting complexes required for transport (ESCRT) proteins, TSG101 and CHMP4b. It was first characterized as an interactor of ALG-2, a calcium-binding protein necessary for cell death, and several observations suggest a role for Alix in controlling cell death. We used electroporation in the chick embryo to test whether overexpressed wild-type or mutated Alix proteins influence cell death in vivo. We show that Alix overexpression is sufficient to induce cell death of neuroepithelial cells. This effect is strictly dependent on its capacity to bind to ALG-2. On the other hand, expression of Alix mutants lacking the ALG-2 or the CHMP4b binding sites prevents early programmed cell death in cervical motoneurons at day 4.5 of chick embryo development. This protection afforded by Alix mutants was abolished after deletion of the TSG101, but not of the endophilin, binding sites. Our results suggest that the interaction of the ALG-2/Alix complex with ESCRT proteins is necessary for naturally occurring death of motoneurons. Therefore, Alix represents a molecular link between the endolysosomal system and the cell death machinery.