Folliculin, a tumor suppressor associated with Birt-Hogg-Dube (BHD) syndrome, is a novel modifier of TDP-43 cytoplasmic translocation and aggregation
Folliculin, a tumor suppressor associated with Birt-Hogg-Dube (BHD) syndrome, is a novel modifier of TDP-43 cytoplasmic translocation and aggregation
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毛囊素是一种与 Birt-Hogg-Dube (BHD) 综合征相关的肿瘤抑制因子，是 TDP-43 细胞质易位和聚集的新型修饰剂
DOI：
10.1093/hmg/ddv450
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发表时间：
2016
影响因子：
3.5
通讯作者：
Ying Zheng
中科院分区：
文献类型：
--
作者：
Xia Qin;Wang Guanghui;Wang Hongfeng;Hu Qingsong;Ying Zheng
TDP-43 被确定为大多数肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTLD) 患者神经元中泛素和自噬体阳性细胞质包涵体的主要成分。研究表明，核 TDP-43 的缺失与 TDP-43 细胞质错误定位的增强（与细胞质中 TDP-43 聚集体的积累有关）是 TDP-43 介导的神经变性的早期关键事件。然而，TDP-43核质穿梭的机制仍不清楚。在这里，我们证明肿瘤抑制滤泡素（FLCN）是 TDP-43 细胞质易位的新型正调节因子。 FLCN 直接与 TDP-43 相互作用。 FLCN 的氨基酸 202-299 和 TDP-43 的 RNA 识别基序结构域对于它们的相互作用是必需的。此外，TDP-43 细胞质积累、蛋白质聚集和应激颗粒形成都需要外源和内源 FLCN。总的来说，我们的研究表明 FLCN 可能在 TDP-43 核质穿梭和 TDP-43 介导的蛋白质病的调节中发挥重要作用。
TDP-43 was identified as the major component of ubiquitin and autophagosome-positive cytoplasmic inclusions in neurons in the large majority of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD) patients. It has been shown that a loss of nuclear TDP-43 in combination with enhanced cytoplasmic mislocalization of TDP-43, which is associated with accumulation of TDP-43 aggregates in the cytosol, is an early and key event in TDP-43-mediated neurodegeneration. However, the mechanism underlying TDP-43 nucleocytoplasmic shuttling is still not clear. Here, we show that the tumor suppressor folliculin (FLCN) is a novel positive regulator of TDP-43 cytoplasmic translocation. FLCN directly interacts with TDP-43. The amino acids 202–299 of FLCN and RNA-recognition motif domains of TDP-43 are necessary for their interaction. In addition, both exogenous and endogenous FLCNs are required for TDP-43 cytoplasmic accumulation, protein aggregation and stress granule formation. Overall, our study suggests that FLCN may play an important role in the regulation of TDP-43 nucleocytoplasmic shuttling and TDP-43-mediated proteinopathy.