The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway.
The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway.
复制标题
DOI：
10.1186/s40478-016-0324-5
复制
发表时间：
2016-05-18
影响因子：
7.1
通讯作者：
Hu F
中科院分区：
文献类型：
--
作者：
Sullivan PM;Zhou X;Robins AM;Paushter DH;Kim D;Smolka MB;Hu F
C9 orf 72基因中的六核苷酸重复扩增是额颞叶变性（FTLD）伴肌萎缩侧索硬化（ALS）的主要原因。C9 orf 72的表达减少被认为是一种可能的疾病机制。然而，C9 orf 72的细胞功能仍有待表征。在这里，我们报告了C9 orf 72的两个结合伴侣的鉴定：SMCR 8和WDR 41。我们发现WDR 41与C9 orf 72/SMCR 8异二聚体相互作用，并且WDR 41与高尔基复合体紧密相关。我们进一步证明了C9 orf 72/SMCR 8/WDR 41与FIP 200/Ulk 1复合物相关，这对自噬启动至关重要。使用CRISPR/Cas9系统产生的C9 orf 72缺陷小鼠在多个器官中显示出严重的炎症，包括淋巴结，脾脏和肝脏。淋巴结肿大和严重的脾肿大伴有巨噬细胞浸润。在C9 orf 72缺陷小鼠的脾脏和肝脏中检测到自噬和溶酶体蛋白水平增加以及自噬缺陷，支持C9 orf 72在调节自噬/溶酶体途径中的体内作用。总之，我们的研究阐明了C9 orf 72的潜在生理功能和ALS/FTLD的发病机制。本文的在线版本（doi：10.1186/s40478-016-0324-5）包含补充材料，可供授权用户使用。
Hexanucleotide repeat expansion in the C9orf72 gene is a leading cause of frontotemporal lobar degeneration (FTLD) with amyotrophic lateral sclerosis (ALS). Reduced expression of C9orf72 has been proposed as a possible disease mechanism. However, the cellular function of C9orf72 remains to be characterized. Here we report the identification of two binding partners of C9orf72: SMCR8 and WDR41. We show that WDR41 interacts with the C9orf72/SMCR8 heterodimer and WDR41 is tightly associated with the Golgi complex. We further demonstrate that C9orf72/SMCR8/WDR41 associates with the FIP200/Ulk1 complex, which is essential for autophagy initiation. C9orf72 deficient mice, generated using the CRISPR/Cas9 system, show severe inflammation in multiple organs, including lymph node, spleen and liver. Lymph node enlargement and severe splenomegaly are accompanied with macrophage infiltration. Increased levels of autophagy and lysosomal proteins and autophagy defects were detected in both the spleen and liver of C9orf72 deficient mice, supporting an in vivo role of C9orf72 in regulating the autophagy/lysosome pathway. In summary, our study elucidates potential physiological functions of C9orf72 and disease mechanisms of ALS/FTLD. The online version of this article (doi:10.1186/s40478-016-0324-5) contains supplementary material, which is available to authorized users.