Jia Zexiao, Yang Shuxu, Li Mengyao, Lei Zhaoying, Ding Xue, Fan Mingjie, Wang Dixian, Xie Dajiang, Zhou Hui, Qiu Yue, Zhuang Qianqian, Li Dan, Yang Wei, Qi Xuchen, Cang Xiaohui, Zhao Jing-Wei, Wang Wenqi, Lin Aifu, Yan Qingfeng
College of Life Sciences Zhejiang University, Zhejiang 310058, China.
Department of Neurosurgery Sir Run Run Shaw Hospital, School of Medicine Zhejiang University, Zhejiang 310016, China.
iScience. 2022 Oct 4;25(11):105275. doi: 10.1016/j.isci.2022.105275. eCollection 2022 Nov 18.
Neurofibromatosis type 2 is an autosomal dominant multiple neoplasia syndrome and is usually caused by mutations in the neurofibromin 2 () gene, which encodes a tumor suppressor and initiates the Hippo pathway. However, the mechanism by which NF2 functions in the Hippo pathway isn't fully understood. Here we identified a c.770-784del mutation from a neurofibromatosis type 2 family. MD simulations showed that this mutation significantly changed the structure of the F3 module of the NF2-FERM domain. Functional assays indicated that the NF2 c.770-784del variant formed LLPS in the cytoplasm with LATS to restrain LATS plasma membrane localization and inactivated the Hippo pathway. Besides, this deletion partly caused a skipping of exon 8 and reduced the protein level of NF2, collectively promoting proliferation and tumorigenesis of meningeal cells. We identified an unrecognized mechanism of LLPS and splicing skipping for the NF2-induced Hippo pathway, which provided new insight into the pathogenesis of neurofibromatosis type 2.
2型神经纤维瘤病是一种常染色体显性多发性肿瘤综合征，通常由神经纤维瘤蛋白2（NF2）基因突变引起，该基因编码一种肿瘤抑制因子并启动Hippo信号通路。然而，NF2在Hippo信号通路中的作用机制尚未完全明确。在此，我们从一个2型神经纤维瘤病家族中鉴定出一个c.770-784del突变。分子动力学模拟表明，该突变显著改变了NF2-FERM结构域F3模块的结构。功能分析表明，NF2 c.770-784del变异体在细胞质中与大肿瘤抑制因子1（LATS）形成液-液相分离（LLPS），从而抑制LATS在质膜上的定位并使Hippo信号通路失活。此外，这种缺失部分导致外显子8跳跃，并降低了NF2的蛋白水平，共同促进脑膜细胞的增殖和肿瘤发生。我们鉴定出一种NF2诱导的Hippo信号通路中尚未被认识的LLPS和剪接跳跃机制，这为2型神经纤维瘤病的发病机制提供了新的见解。
Zotero 插件
