Nuclear Condensates of WW Domain‐Containing Adaptor With Coiled‐Coil Regulate Mitophagy via Alternative Splicing
Abstract Biomolecular condensates segregate nuclei into discrete regions, facilitating the execution of distinct biological functions. Here, it is identified that the WW domain containing adaptor with coiled‐coil (WAC) is localized to nuclear speckles via its WW domain and plays a pivotal role in re...
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| Format: | Article |
| Language: | English |
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Wiley
2025-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202406759 |
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| author | Jiahe Wang Yi Fan Guowen Luo Liang Xiong Lijie Wang Zhuoxuan Wu Jiayi Wang Zhengying Peng Clifford J Rosen Kefeng Lu Junjun Jing Quan Yuan Zhenwei Zhang Chenchen Zhou |
| author_facet | Jiahe Wang Yi Fan Guowen Luo Liang Xiong Lijie Wang Zhuoxuan Wu Jiayi Wang Zhengying Peng Clifford J Rosen Kefeng Lu Junjun Jing Quan Yuan Zhenwei Zhang Chenchen Zhou |
| author_sort | Jiahe Wang |
| collection | DOAJ |
| description | Abstract Biomolecular condensates segregate nuclei into discrete regions, facilitating the execution of distinct biological functions. Here, it is identified that the WW domain containing adaptor with coiled‐coil (WAC) is localized to nuclear speckles via its WW domain and plays a pivotal role in regulating alternative splicing through the formation of biomolecular condensates via its C‐terminal coiled‐coil (CC) domain. WAC acts as a scaffold protein and facilitates the integration of RNA‐binding motif 12 (RBM12) into nuclear speckles, where RBM12 potentially interacts with the spliceosomal U5 small nuclear ribonucleoprotein (snRNP). Importantly, knockdown of RBM12, or deletion of the WAC CC domain led to altered splicing outcomes, resulting in an elevated level of BECN1‐S, the short splice variant of BECN1 that is shown to upregulate mitophagy. Thus, the findings reveal a previously unrecognized mechanism for the nuclear regulation of mitochondrial function through liquid–liquid phase separation (LLPS) and provide insights into the pathogenesis of WAC‐related disorders. |
| format | Article |
| id | doaj-art-554b140996c547e79391ecfdabe38bcc |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-554b140996c547e79391ecfdabe38bcc2025-08-20T02:35:40ZengWileyAdvanced Science2198-38442025-03-011210n/an/a10.1002/advs.202406759Nuclear Condensates of WW Domain‐Containing Adaptor With Coiled‐Coil Regulate Mitophagy via Alternative SplicingJiahe Wang0Yi Fan1Guowen Luo2Liang Xiong3Lijie Wang4Zhuoxuan Wu5Jiayi Wang6Zhengying Peng7Clifford J Rosen8Kefeng Lu9Junjun Jing10Quan Yuan11Zhenwei Zhang12Chenchen Zhou13State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University Chengdu 610041 ChinaState Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University Chengdu 610041 ChinaState Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University Chengdu 610041 ChinaState Key Laboratory of Biotherapy and Department of Rheumatology and Immunology West China Hospital Sichuan University Chengdu 610041 ChinaState Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University Chengdu 610041 ChinaState Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University Chengdu 610041 ChinaState Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University Chengdu 610041 ChinaState Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University Chengdu 610041 ChinaMaine Medical Center Research Institute Scarborough ME 04074 USADepartment of Neurosurgery State Key Laboratory of Biotherapy West China Hospital Sichuan University and The Research Units of West China Chinese Academy of Medical Sciences Chengdu 610041 ChinaState Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University Chengdu 610041 ChinaState Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University Chengdu 610041 ChinaState Key Laboratory of Biotherapy and Department of Rheumatology and Immunology West China Hospital Sichuan University Chengdu 610041 ChinaState Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases West China Hospital of Stomatology Sichuan University Chengdu 610041 ChinaAbstract Biomolecular condensates segregate nuclei into discrete regions, facilitating the execution of distinct biological functions. Here, it is identified that the WW domain containing adaptor with coiled‐coil (WAC) is localized to nuclear speckles via its WW domain and plays a pivotal role in regulating alternative splicing through the formation of biomolecular condensates via its C‐terminal coiled‐coil (CC) domain. WAC acts as a scaffold protein and facilitates the integration of RNA‐binding motif 12 (RBM12) into nuclear speckles, where RBM12 potentially interacts with the spliceosomal U5 small nuclear ribonucleoprotein (snRNP). Importantly, knockdown of RBM12, or deletion of the WAC CC domain led to altered splicing outcomes, resulting in an elevated level of BECN1‐S, the short splice variant of BECN1 that is shown to upregulate mitophagy. Thus, the findings reveal a previously unrecognized mechanism for the nuclear regulation of mitochondrial function through liquid–liquid phase separation (LLPS) and provide insights into the pathogenesis of WAC‐related disorders.https://doi.org/10.1002/advs.202406759mitophagynuclear specklesphase‐separated biomolecular condensatespre‐mRNA splicingsnRNPWAC |
| spellingShingle | Jiahe Wang Yi Fan Guowen Luo Liang Xiong Lijie Wang Zhuoxuan Wu Jiayi Wang Zhengying Peng Clifford J Rosen Kefeng Lu Junjun Jing Quan Yuan Zhenwei Zhang Chenchen Zhou Nuclear Condensates of WW Domain‐Containing Adaptor With Coiled‐Coil Regulate Mitophagy via Alternative Splicing Advanced Science mitophagy nuclear speckles phase‐separated biomolecular condensates pre‐mRNA splicing snRNP WAC |
| title | Nuclear Condensates of WW Domain‐Containing Adaptor With Coiled‐Coil Regulate Mitophagy via Alternative Splicing |
| title_full | Nuclear Condensates of WW Domain‐Containing Adaptor With Coiled‐Coil Regulate Mitophagy via Alternative Splicing |
| title_fullStr | Nuclear Condensates of WW Domain‐Containing Adaptor With Coiled‐Coil Regulate Mitophagy via Alternative Splicing |
| title_full_unstemmed | Nuclear Condensates of WW Domain‐Containing Adaptor With Coiled‐Coil Regulate Mitophagy via Alternative Splicing |
| title_short | Nuclear Condensates of WW Domain‐Containing Adaptor With Coiled‐Coil Regulate Mitophagy via Alternative Splicing |
| title_sort | nuclear condensates of ww domain containing adaptor with coiled coil regulate mitophagy via alternative splicing |
| topic | mitophagy nuclear speckles phase‐separated biomolecular condensates pre‐mRNA splicing snRNP WAC |
| url | https://doi.org/10.1002/advs.202406759 |
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