Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Stanford Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Brain Res. 2020 Feb 1;1728:146601. doi: 10.1016/j.brainres.2019.146601. Epub 2019 Dec 13.
Mutations in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis (ALS). Both toxic gain of function and loss of function pathogenic mechanisms have been proposed. Accruing evidence from mouse knockout studies point to a role for C9ORF72 as a regulator of immune function. To provide further insight into its cellular function, we performed a genome-wide synthetic lethal CRISPR screen in human myeloid cells lacking C9ORF72. We discovered a strong synthetic lethal genetic interaction between C9ORF72 and FIS1, which encodes a mitochondrial membrane protein involved in mitochondrial fission and mitophagy. Mass spectrometry experiments revealed that in C9ORF72 knockout cells, FIS1 strongly bound to a class of immune regulators that activate the receptor for advanced glycation end (RAGE) products and trigger inflammatory cascades. These findings present a novel genetic interactor for C9ORF72 and suggest a compensatory role for FIS1 in suppressing inflammatory signaling in the absence of C9ORF72.
C9ORF72 基因突变是肌萎缩侧索硬化症（ALS）最常见的原因。目前已经提出了毒性获得功能和功能丧失致病机制。来自小鼠敲除研究的越来越多的证据表明，C9ORF72 作为免疫功能的调节剂发挥作用。为了更深入地了解其细胞功能，我们在缺乏 C9ORF72 的人类髓样细胞中进行了全基因组合成致死 CRISPR 筛选。我们发现 C9ORF72 和 FIS1 之间存在强烈的合成致死遗传相互作用，FIS1 编码一种参与线粒体分裂和线粒体自噬的线粒体膜蛋白。质谱实验表明，在 C9ORF72 敲除细胞中，FIS1 与一类免疫调节剂强烈结合，这些调节剂激活晚期糖基化终产物（RAGE）产物的受体并触发炎症级联反应。这些发现为 C9ORF72 提供了一个新的遗传相互作用因子，并表明在缺乏 C9ORF72 的情况下，FIS1 发挥代偿作用以抑制炎症信号。
