Sardina Francesca, Polverino Federica, Valentini Sonia, Carsetti Claudia, Falvo Elisabetta, Tisci Giada, Soddu Silvia, Moretti Fabiola, Paiardini Alessandro, Rinaldo Cinzia
Institute of Molecular Biology and Pathology, Italian National Research Council, c/o Sapienza University, Rome, Italy.
Institute of Biochemistry and Cell Biology, Italian National Research Council, Rome, Italy.
Cell Death Discov. 2025 Feb 7;11(1):53. doi: 10.1038/s41420-025-02333-y.
Spastin is a microtubule (MT) severing enzyme that regulates several cell functions associated with MT dynamics. A reduction in spastin protein levels is responsible for approximately 40% of cases of Hereditary Spastic Paraplegia (HSP), a neurodegenerative disease. Currently, there is no cure for HSP but strategies to induce a recovery of spastin levels are emerging as potential therapeutic approaches. Here, we show that MDM2 interacts with spastin MT-interacting and trafficking (MIT) domain. By biochemical and functional experiments, we demonstrate that MDM2 binds spastin and regulates its levels in a post-transcriptional manner independently of the E3 ubiquitin ligase activity. Of relevance, treatment of spastin-deficient cells with the MDM2 inhibitor Nutlin-3a can restore spastin levels and functions, such as cytokinetic abscission and sorting of transferrin receptor. These findings identify MDM2 as a novel interactor of spastin and a potential druggable regulator of its protein levels.
痉挛素是一种微管（MT）切断酶，可调节与MT动态相关的多种细胞功能。痉挛素蛋白水平降低约占遗传性痉挛性截瘫（HSP）病例的40%，HSP是一种神经退行性疾病。目前，HSP尚无治愈方法，但诱导痉挛素水平恢复的策略正作为潜在的治疗方法出现。在此，我们表明MDM2与痉挛素的微管相互作用及运输（MIT）结构域相互作用。通过生化和功能实验，我们证明MDM2结合痉挛素并以转录后方式独立于E3泛素连接酶活性调节其水平。相关的是，用MDM2抑制剂Nutlin-3a处理痉挛素缺陷细胞可恢复痉挛素水平和功能，如细胞分裂期脱离和转铁蛋白受体分选。这些发现确定MDM2是痉挛素的一种新型相互作用蛋白及其蛋白水平的潜在可药物调节因子。
