The Cullin3–Ring E3 ubiquitin ligase complex and USP14 regulate spastin-mediated microtubule severing and promotion of neurite outgrowth
Post-translational modification of spastin enables precise spatiotemporal control of its microtubule severing activity. However, the detailed mechanism by which spastin turnover is regulated in the context of neurite outgrowth remains unknown. Here, we found that spastin interacted with ubiquitin an...
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Medknow Publications
2026-04-01
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| Series: | Neural Regeneration Research |
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| Online Access: | https://journals.lww.com/10.4103/NRR.NRR-D-25-00037 |
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| author | Zhenbin Cai Hui Wu Tao Jiang Ao Ma Zhichao Meng Jiehao Zhu Hongsheng Lin Yaozhong Liang Guowei Zhang Minghui Tan |
| author_facet | Zhenbin Cai Hui Wu Tao Jiang Ao Ma Zhichao Meng Jiehao Zhu Hongsheng Lin Yaozhong Liang Guowei Zhang Minghui Tan |
| author_sort | Zhenbin Cai |
| collection | DOAJ |
| description | Post-translational modification of spastin enables precise spatiotemporal control of its microtubule severing activity. However, the detailed mechanism by which spastin turnover is regulated in the context of neurite outgrowth remains unknown. Here, we found that spastin interacted with ubiquitin and was significantly degraded by K48-mediated poly-ubiquitination. Cullin3 facilitated spastin degradation and ubiquitination. RING-box protein 1, but not RING-box protein 2, acted synergistically with Cullin3 protein to regulate spastin degradation. Overexpression of Culin3 or BRX1 markedly suppressed spastin expression, and inhibited spastin-mediated microtubule severing and promotion of neurite outgrowth. Moreover, USP14 interacted directly with spastin to mediate its de-ubiquitination. USP14 overexpression significantly increased spastin expression and suppressed its ubiquitination and degradation. Although co-expression of spastin and USP14 did not enhance microtubule severing, it did increase neurite length in hippocampal neurons. Taken together, these findings elucidate the intricate regulatory mechanisms of spastin turnover, highlighting the roles of the Cullin-3–Ring E3 ubiquitin ligase complex and USP14 in orchestrating its ubiquitination and degradation. The dynamic interplay between these factors governs spastin stability and function, ultimately influencing microtubule dynamics and neuronal morphology. These insights shed light on potential therapeutic targets for neurodegenerative disorders associated with spastin defects. |
| format | Article |
| id | doaj-art-5f985a66dd9b4e9386812183ec4eeb4b |
| institution | Kabale University |
| issn | 1673-5374 1876-7958 |
| language | English |
| publishDate | 2026-04-01 |
| publisher | Wolters Kluwer Medknow Publications |
| record_format | Article |
| series | Neural Regeneration Research |
| spelling | doaj-art-5f985a66dd9b4e9386812183ec4eeb4b2025-08-20T03:31:40ZengWolters Kluwer Medknow PublicationsNeural Regeneration Research1673-53741876-79582026-04-012141641165110.4103/NRR.NRR-D-25-00037The Cullin3–Ring E3 ubiquitin ligase complex and USP14 regulate spastin-mediated microtubule severing and promotion of neurite outgrowthZhenbin CaiHui WuTao JiangAo MaZhichao MengJiehao ZhuHongsheng LinYaozhong LiangGuowei ZhangMinghui TanPost-translational modification of spastin enables precise spatiotemporal control of its microtubule severing activity. However, the detailed mechanism by which spastin turnover is regulated in the context of neurite outgrowth remains unknown. Here, we found that spastin interacted with ubiquitin and was significantly degraded by K48-mediated poly-ubiquitination. Cullin3 facilitated spastin degradation and ubiquitination. RING-box protein 1, but not RING-box protein 2, acted synergistically with Cullin3 protein to regulate spastin degradation. Overexpression of Culin3 or BRX1 markedly suppressed spastin expression, and inhibited spastin-mediated microtubule severing and promotion of neurite outgrowth. Moreover, USP14 interacted directly with spastin to mediate its de-ubiquitination. USP14 overexpression significantly increased spastin expression and suppressed its ubiquitination and degradation. Although co-expression of spastin and USP14 did not enhance microtubule severing, it did increase neurite length in hippocampal neurons. Taken together, these findings elucidate the intricate regulatory mechanisms of spastin turnover, highlighting the roles of the Cullin-3–Ring E3 ubiquitin ligase complex and USP14 in orchestrating its ubiquitination and degradation. The dynamic interplay between these factors governs spastin stability and function, ultimately influencing microtubule dynamics and neuronal morphology. These insights shed light on potential therapeutic targets for neurodegenerative disorders associated with spastin defects.https://journals.lww.com/10.4103/NRR.NRR-D-25-00037cullin3microtubule severingneurite outgrowthprotein degradationspastinubiquitinationusp14 |
| spellingShingle | Zhenbin Cai Hui Wu Tao Jiang Ao Ma Zhichao Meng Jiehao Zhu Hongsheng Lin Yaozhong Liang Guowei Zhang Minghui Tan The Cullin3–Ring E3 ubiquitin ligase complex and USP14 regulate spastin-mediated microtubule severing and promotion of neurite outgrowth Neural Regeneration Research cullin3 microtubule severing neurite outgrowth protein degradation spastin ubiquitination usp14 |
| title | The Cullin3–Ring E3 ubiquitin ligase complex and USP14 regulate spastin-mediated microtubule severing and promotion of neurite outgrowth |
| title_full | The Cullin3–Ring E3 ubiquitin ligase complex and USP14 regulate spastin-mediated microtubule severing and promotion of neurite outgrowth |
| title_fullStr | The Cullin3–Ring E3 ubiquitin ligase complex and USP14 regulate spastin-mediated microtubule severing and promotion of neurite outgrowth |
| title_full_unstemmed | The Cullin3–Ring E3 ubiquitin ligase complex and USP14 regulate spastin-mediated microtubule severing and promotion of neurite outgrowth |
| title_short | The Cullin3–Ring E3 ubiquitin ligase complex and USP14 regulate spastin-mediated microtubule severing and promotion of neurite outgrowth |
| title_sort | cullin3 ring e3 ubiquitin ligase complex and usp14 regulate spastin mediated microtubule severing and promotion of neurite outgrowth |
| topic | cullin3 microtubule severing neurite outgrowth protein degradation spastin ubiquitination usp14 |
| url | https://journals.lww.com/10.4103/NRR.NRR-D-25-00037 |
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