中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (4): 1641-1651.doi: 10.4103/NRR.NRR-D-25-00037

• 原著:退行性病与再生 • 上一篇    下一篇

Cullin3-Ring E3泛素连接酶与USP14介导Spastin泛素/去泛素化修饰调控微管切割和神经元生长的新机制

  

  • 出版日期:2026-04-15 发布日期:2025-07-28
  • 基金资助:
    国家自然科学基金（32071033）、广东省基础与应用基础研究基金（2023A1515010140、2022A1515140169、2022A1515111096）、广州市科技专项（202201010015、2023A03J0790）、广州市基础与应用基础研究基金（2023A04J1285）、广东省医学科研基金项目（A2023147）、广州市卫生科技计划项目（20221A011039)。

The Cullin3–Ring E3 ubiquitin ligase complex and USP14 regulate spastin-mediated microtubule severing and promotion of neurite outgrowth

Zhenbin Cai1, #, Hui Wu1, #, Tao Jiang2, #, Ao Ma1 , Zhichao Meng1 , Jiehao Zhu1 , Hongsheng Lin1 , Yaozhong Liang1, *, Guowei Zhang1, *, Minghui Tan1, *   

  1. 1 Department of Orthopedics, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China;  2 Department of Orthopedics, Guangzhou Eighth People’s Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China
  • Online:2026-04-15 Published:2025-07-28
  • Contact: Guowei Zhang, MD, zgw24@jnu.edu.cn; Yaozhong Liang, MD, tliangyz@jnu.edu.cn; Minghui Tan, PhD, tanminghui@jnu.edu.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, No. 32071033 (to MT); Basic and Applied Basic Research Foundation of Guangdong Province, Nos. 2023A1515010140 (to MT), 2022A1515140169 (to MT), 2022A1515111096 (to ZC); Science and Technology Project of Guangzhou, Nos. 202201010015 (to YL), 2023A03J0790 (to TJ); Basic and Applied Basic Research Foundation of Guangzhou, No. 2023A04J1285 (to ZC); Medical Research Foundation of Guangdong Province, No. A2023147 (to ZC); and Health Science and Technology Project of Guangzhou, No. 20221A011039 (to TJ).

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摘要：

微管切割蛋白Spastin的后修饰导致了对微管切断活性的精确时空控制。然而，在神经元生长过程中，Spastin 蛋白更替的详细机制仍不清楚。实验发现spastin与泛素相互作用，并通过K48介导的多泛素化显著降解。Cullin3促进了Spastin的降解和泛素化。RBX1（而非RBX2）与Cullin3蛋白共同调控Spastin的降解。过量表达Culin3或BRX1都会显著抑制spastin的蛋白水平，并抑制Spastin介导的微管切断和促进神经元生长的作用。此外，还发现 USP14 介导了 spastin 的去泛素化。USP14 与 Spastin 相互作用。过量表达 USP14 能显著提高蛋白水平，抑制 Spastin 的泛素化和降解。虽然Spastin和USP14的共同表达并不能增强微管的切断，但却能增加海马神经元的神经元长度。总之，实验结果阐明了Spastin周转的复杂调控机制，强调了Cullin-3-Ring E3泛素连接酶复合物和USP14在协调其降解和泛素化调控中的作用。这些因素之间的动态相互作用决定了海绵蛋白的稳定性和功能性，并最终影响微管动力学和神经元形态。这些发现为Spastin相关神经退行性疾病的治疗提供了新的分子机制和潜在干预策略。

https://orcid.org/000-0002-1655-6498 (Guowei Zhang); https://orcid.org/0009-0003-1884-7648 (Yaozhong Liang); https://orcid.org/0000-0001-6260-4115 (Minghui Tan)

关键词: Cullin3, 微管切断, 神经元突起, 蛋白质降解, Spastin, 泛素化, USP14

Abstract: 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 deubiquitination. 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.

Key words: Cullin3, microtubule severing, neurite outgrowth, protein degradation, spastin, ubiquitination, USP14