TSPYL5-driven G3BP1 nuclear membrane translocation facilitates p53 cytoplasm sequestration via accelerating RanBP2-mediated p53 sumoylation and nuclear export in neuroblastoma
Abstract Cytoplasmic sequestration of wild-type p53, representing a nonmutational event of p53 activity suppression, is a characteristic phenotype of undifferentiated neuroblastoma (NB); however, the underlying mechanism is yet to be defined. In the present study, we observed that TSPYL5 effectively...
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Nature Publishing Group
2025-05-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07694-x |
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| author | Zhaokun Wang Yunqiang Liu Yangwei Zhang Jiaying Shi Shengyu Xie Ming Yi Xinyue Zhang Dachang Tao Yuan Yang |
| author_facet | Zhaokun Wang Yunqiang Liu Yangwei Zhang Jiaying Shi Shengyu Xie Ming Yi Xinyue Zhang Dachang Tao Yuan Yang |
| author_sort | Zhaokun Wang |
| collection | DOAJ |
| description | Abstract Cytoplasmic sequestration of wild-type p53, representing a nonmutational event of p53 activity suppression, is a characteristic phenotype of undifferentiated neuroblastoma (NB); however, the underlying mechanism is yet to be defined. In the present study, we observed that TSPYL5 effectively tethers p53 in the cytoplasm and greatly inhibits its function as a transcription factor. Mechanistically, the binding of TSPYL5 with G3BP1 enhances G3BP1 Ser149 phosphorylation to drive G3BP1 nuclear membrane translocation, which recruits more p53 for nucleoporin RanBP2 by the formation of the RanBP2-G3BP1-p53 complex. Thus, the accelerating p53 sumoylation promotes its nuclear export. With this signal pathway, TSPYL5 augments the malignant characteristics of neuroblastoma cells. Our findings unravel a detailed TSPYL5-driven molecular axis that sheds light on the regulating system of the p53 sumoylation-based cytoplasmic sequestration in NB cells, paving the way for the novel therapeutic opportunities for NB cancers by antagonizing TSPYL5 function. |
| format | Article |
| id | doaj-art-2b9f8691239d4d418ef8154606e69c47 |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death and Disease |
| spelling | doaj-art-2b9f8691239d4d418ef8154606e69c472025-08-20T02:10:53ZengNature Publishing GroupCell Death and Disease2041-48892025-05-0116111310.1038/s41419-025-07694-xTSPYL5-driven G3BP1 nuclear membrane translocation facilitates p53 cytoplasm sequestration via accelerating RanBP2-mediated p53 sumoylation and nuclear export in neuroblastomaZhaokun Wang0Yunqiang Liu1Yangwei Zhang2Jiaying Shi3Shengyu Xie4Ming Yi5Xinyue Zhang6Dachang Tao7Yuan Yang8Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityAbstract Cytoplasmic sequestration of wild-type p53, representing a nonmutational event of p53 activity suppression, is a characteristic phenotype of undifferentiated neuroblastoma (NB); however, the underlying mechanism is yet to be defined. In the present study, we observed that TSPYL5 effectively tethers p53 in the cytoplasm and greatly inhibits its function as a transcription factor. Mechanistically, the binding of TSPYL5 with G3BP1 enhances G3BP1 Ser149 phosphorylation to drive G3BP1 nuclear membrane translocation, which recruits more p53 for nucleoporin RanBP2 by the formation of the RanBP2-G3BP1-p53 complex. Thus, the accelerating p53 sumoylation promotes its nuclear export. With this signal pathway, TSPYL5 augments the malignant characteristics of neuroblastoma cells. Our findings unravel a detailed TSPYL5-driven molecular axis that sheds light on the regulating system of the p53 sumoylation-based cytoplasmic sequestration in NB cells, paving the way for the novel therapeutic opportunities for NB cancers by antagonizing TSPYL5 function.https://doi.org/10.1038/s41419-025-07694-x |
| spellingShingle | Zhaokun Wang Yunqiang Liu Yangwei Zhang Jiaying Shi Shengyu Xie Ming Yi Xinyue Zhang Dachang Tao Yuan Yang TSPYL5-driven G3BP1 nuclear membrane translocation facilitates p53 cytoplasm sequestration via accelerating RanBP2-mediated p53 sumoylation and nuclear export in neuroblastoma Cell Death and Disease |
| title | TSPYL5-driven G3BP1 nuclear membrane translocation facilitates p53 cytoplasm sequestration via accelerating RanBP2-mediated p53 sumoylation and nuclear export in neuroblastoma |
| title_full | TSPYL5-driven G3BP1 nuclear membrane translocation facilitates p53 cytoplasm sequestration via accelerating RanBP2-mediated p53 sumoylation and nuclear export in neuroblastoma |
| title_fullStr | TSPYL5-driven G3BP1 nuclear membrane translocation facilitates p53 cytoplasm sequestration via accelerating RanBP2-mediated p53 sumoylation and nuclear export in neuroblastoma |
| title_full_unstemmed | TSPYL5-driven G3BP1 nuclear membrane translocation facilitates p53 cytoplasm sequestration via accelerating RanBP2-mediated p53 sumoylation and nuclear export in neuroblastoma |
| title_short | TSPYL5-driven G3BP1 nuclear membrane translocation facilitates p53 cytoplasm sequestration via accelerating RanBP2-mediated p53 sumoylation and nuclear export in neuroblastoma |
| title_sort | tspyl5 driven g3bp1 nuclear membrane translocation facilitates p53 cytoplasm sequestration via accelerating ranbp2 mediated p53 sumoylation and nuclear export in neuroblastoma |
| url | https://doi.org/10.1038/s41419-025-07694-x |
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