PDF(Pubmed)
Abstract：
The organelle contact site of the endoplasmic reticulum and mitochondria, known as the mitochondria-associated membrane (MAM), is a multifunctional microdomain in cellular homeostasis. We previously reported that MAM disruption is a common pathological feature in amyotrophic lateral sclerosis (ALS); however, the precise role of MAM in ALS was uncovered. Here, we show that the MAM is essential for TANK-binding kinase 1 (TBK1) activation under proteostatic stress conditions. A MAM-specific E3 ubiquitin ligase, autocrine motility factor receptor, ubiquitinated nascent proteins to activate TBK1 at the MAM, which results in ribosomal protein degradation. MAM or TBK1 deficiency under proteostatic stress conditions resulted in increased cellular vulnerability in vitro and motor impairment in vivo. Thus, MAM disruption exacerbates proteostatic stress via TBK1 inactivation in ALS. Our study has revealed a proteostatic mechanism mediated by the MAM-TBK1 axis, highlighting the physiological importance of the organelle contact sites.
摘要：
内质网和线粒体的细胞器接触位点，称为线粒体相关膜（MAM），是细胞稳态中的多功能微域。我们以前报道过，MAM破坏是肌萎缩侧索硬化症（ALS）的常见病理特征；然而，发现了MAM在ALS中的确切作用。这里,我们表明，MAM对于TANK结合激酶1（TBK1）在蛋白抑制应激条件下的激活是必不可少的。MAM特异性E3泛素连接酶，自分泌运动因子受体，泛素化新生蛋白在MAM激活TBK1，导致核糖体蛋白降解。在蛋白抑制应激条件下的MAM或TBK1缺乏导致体外细胞易损性增加和体内运动障碍。因此，MAM破坏通过ALS中的TBK1失活加剧了蛋白抑制应激。我们的研究揭示了由MAM-TBK1轴介导的蛋白抑制机制，强调细胞器接触部位的生理重要性。
