A novel NF2 splicing mutant causes neurofibromatosis type 2 via liquid-liquid phase separation with large tumor suppressor and Hippo pathway

Neurofibromatosis type 2 is an autosomal dominant multiple neoplasia syndrome and is usually caused by mutations in the neurofibromin 2 (NF2) 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 underst...

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Veröffentlicht in:iScience 2022-11, Vol.25 (11), p.105275-105275, Article 105275
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung:Neurofibromatosis type 2 is an autosomal dominant multiple neoplasia syndrome and is usually caused by mutations in the neurofibromin 2 (NF2) 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 NF2 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. [Display omitted] •NF2 c.770-784 deletion is a novel mutation related to Neurofibromatosis type 2•NF2 variant forms LLPS in the cytoplasm with LATS and inhibits the Hippo pathway•NF2 variant causes an aberrant skipping of exon 8 and reduces NF2 protein level•NF2 variant promotes proliferation and tumorigenesis of meningeal cells Clinical genetics; Pathophysiology; Functional aspects of cell biology
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2022.105275