A novel NF2 splicing mutant causes neurofibromatosis type 2 via liquid-liquid phase separation with large tumor suppressor and Hippo pathway
Summary: 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 full...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-11-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222015474 |
| _version_ | 1797990505227747328 |
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| author | Zexiao Jia Shuxu Yang Mengyao Li Zhaoying Lei Xue Ding Mingjie Fan Dixian Wang Dajiang Xie Hui Zhou Yue Qiu Qianqian Zhuang Dan Li Wei Yang Xuchen Qi Xiaohui Cang Jing-Wei Zhao Wenqi Wang Aifu Lin Qingfeng Yan |
| author_facet | Zexiao Jia Shuxu Yang Mengyao Li Zhaoying Lei Xue Ding Mingjie Fan Dixian Wang Dajiang Xie Hui Zhou Yue Qiu Qianqian Zhuang Dan Li Wei Yang Xuchen Qi Xiaohui Cang Jing-Wei Zhao Wenqi Wang Aifu Lin Qingfeng Yan |
| author_sort | Zexiao Jia |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-04-11T08:37:38Z |
| format | Article |
| id | doaj.art-645092645f1c450f9456a67337c69fb6 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-11T08:37:38Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-645092645f1c450f9456a67337c69fb62022-12-22T04:34:17ZengElsevieriScience2589-00422022-11-012511105275A novel NF2 splicing mutant causes neurofibromatosis type 2 via liquid-liquid phase separation with large tumor suppressor and Hippo pathwayZexiao Jia0Shuxu Yang1Mengyao Li2Zhaoying Lei3Xue Ding4Mingjie Fan5Dixian Wang6Dajiang Xie7Hui Zhou8Yue Qiu9Qianqian Zhuang10Dan Li11Wei Yang12Xuchen Qi13Xiaohui Cang14Jing-Wei Zhao15Wenqi Wang16Aifu Lin17Qingfeng Yan18College of Life Sciences Zhejiang University, Zhejiang 310058, ChinaDepartment of Neurosurgery Sir Run Run Shaw Hospital, School of Medicine Zhejiang University, Zhejiang 310016, China; Corresponding authorCollege of Life Sciences Zhejiang University, Zhejiang 310058, ChinaCollege of Life Sciences Zhejiang University, Zhejiang 310058, ChinaCollege of Life Sciences Zhejiang University, Zhejiang 310058, ChinaCollege of Life Sciences Zhejiang University, Zhejiang 310058, ChinaSchool of Medicine Zhejiang University, Zhejiang 310058, ChinaDepartment of Neurosurgery Sir Run Run Shaw Hospital, School of Medicine Zhejiang University, Zhejiang 310016, ChinaCollege of Life Sciences Zhejiang University, Zhejiang 310058, ChinaCollege of Life Sciences Zhejiang University, Zhejiang 310058, ChinaCollege of Life Sciences Zhejiang University, Zhejiang 310058, ChinaCollege of Life Sciences Zhejiang University, Zhejiang 310058, ChinaCollege of Life Sciences Zhejiang University, Zhejiang 310058, ChinaDepartment of Neurosurgery Sir Run Run Shaw Hospital, School of Medicine Zhejiang University, Zhejiang 310016, ChinaSchool of Medicine Zhejiang University, Zhejiang 310058, ChinaSchool of Medicine Zhejiang University, Zhejiang 310058, ChinaDepartment of Developmental and Cell Biology, University of California, Irvine, CA 92697, USACollege of Life Sciences Zhejiang University, Zhejiang 310058, China; Corresponding authorCollege of Life Sciences Zhejiang University, Zhejiang 310058, China; Department of Pediatrics, The First Affiliated Hospital, School of Medicine Zhejiang University, Zhejiang 310003, China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Zhejiang 310058, China; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004222015474Clinical geneticsPathophysiologyFunctional aspects of cell biology |
| spellingShingle | Zexiao Jia Shuxu Yang Mengyao Li Zhaoying Lei Xue Ding Mingjie Fan Dixian Wang Dajiang Xie Hui Zhou Yue Qiu Qianqian Zhuang Dan Li Wei Yang Xuchen Qi Xiaohui Cang Jing-Wei Zhao Wenqi Wang Aifu Lin Qingfeng Yan A novel NF2 splicing mutant causes neurofibromatosis type 2 via liquid-liquid phase separation with large tumor suppressor and Hippo pathway iScience Clinical genetics Pathophysiology Functional aspects of cell biology |
| title | A novel NF2 splicing mutant causes neurofibromatosis type 2 via liquid-liquid phase separation with large tumor suppressor and Hippo pathway |
| title_full | A novel NF2 splicing mutant causes neurofibromatosis type 2 via liquid-liquid phase separation with large tumor suppressor and Hippo pathway |
| title_fullStr | A novel NF2 splicing mutant causes neurofibromatosis type 2 via liquid-liquid phase separation with large tumor suppressor and Hippo pathway |
| title_full_unstemmed | A novel NF2 splicing mutant causes neurofibromatosis type 2 via liquid-liquid phase separation with large tumor suppressor and Hippo pathway |
| title_short | A novel NF2 splicing mutant causes neurofibromatosis type 2 via liquid-liquid phase separation with large tumor suppressor and Hippo pathway |
| title_sort | novel nf2 splicing mutant causes neurofibromatosis type 2 via liquid liquid phase separation with large tumor suppressor and hippo pathway |
| topic | Clinical genetics Pathophysiology Functional aspects of cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222015474 |
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