Targeting MDM2 affects spastin protein levels and functions: implications for HSP treatment.

IF 7 2区生物学 Q1 CELL BIOLOGY Cell Death Discovery Pub Date : 2025-02-07 DOI:10.1038/s41420-025-02333-y

Francesca Sardina, Federica Polverino, Sonia Valentini, Claudia Carsetti, Elisabetta Falvo, Giada Tisci, Silvia Soddu, Fabiola Moretti, Alessandro Paiardini, Cinzia Rinaldo

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Abstract

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.

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靶向MDM2影响痉挛蛋白水平和功能：对热休克治疗的影响。

Spastin是一种微管切断酶，调节与微管动力学相关的几种细胞功能。大约40%的遗传性痉挛性截瘫（HSP）是一种神经退行性疾病，痉挛蛋白水平降低是病因。目前，尚无治愈热休克的方法，但诱导痉挛素水平恢复的策略正在成为潜在的治疗方法。在这里，我们发现MDM2与痉挛蛋白mt相互作用和贩运（MIT）结构域相互作用。通过生化和功能实验，我们证明MDM2结合spastin并以独立于E3泛素连接酶活性的转录后方式调节其水平。与此相关的是，用MDM2抑制剂Nutlin-3a治疗痉挛素缺乏的细胞可以恢复痉挛素水平和功能，如细胞动力学脱落和转铁蛋白受体的分选。这些发现表明MDM2是一种新的spastin相互作用物，也是一种潜在的可药物调节其蛋白水平的物质。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.