A novel NF2 splicing mutant causes neurofibromatosis type 2 via liquid-liquid phase separation with large tumor suppressor and Hippo pathway
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
Affiliations
Zexiao Jia
College of Life Sciences Zhejiang University, Zhejiang 310058, China
Shuxu Yang
Department of Neurosurgery Sir Run Run Shaw Hospital, School of Medicine Zhejiang University, Zhejiang 310016, China; Corresponding author
Mengyao Li
College of Life Sciences Zhejiang University, Zhejiang 310058, China
Zhaoying Lei
College of Life Sciences Zhejiang University, Zhejiang 310058, China
Xue Ding
College of Life Sciences Zhejiang University, Zhejiang 310058, China
Mingjie Fan
College of Life Sciences Zhejiang University, Zhejiang 310058, China
Dixian Wang
School of Medicine Zhejiang University, Zhejiang 310058, China
Dajiang Xie
Department of Neurosurgery Sir Run Run Shaw Hospital, School of Medicine Zhejiang University, Zhejiang 310016, China
Hui Zhou
College of Life Sciences Zhejiang University, Zhejiang 310058, China
Yue Qiu
College of Life Sciences Zhejiang University, Zhejiang 310058, China
Qianqian Zhuang
College of Life Sciences Zhejiang University, Zhejiang 310058, China
Dan Li
College of Life Sciences Zhejiang University, Zhejiang 310058, China
Wei Yang
College of Life Sciences Zhejiang University, Zhejiang 310058, China
Xuchen Qi
Department of Neurosurgery Sir Run Run Shaw Hospital, School of Medicine Zhejiang University, Zhejiang 310016, China
Xiaohui Cang
School of Medicine Zhejiang University, Zhejiang 310058, China
Jing-Wei Zhao
School of Medicine Zhejiang University, Zhejiang 310058, China
Wenqi Wang
Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA
Aifu Lin
College of Life Sciences Zhejiang University, Zhejiang 310058, China; Corresponding author
Qingfeng Yan
College 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 author
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.
