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SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution
Molecular Neurobiology ( IF 5.1 ) Pub Date : 2021-08-14 , DOI: 10.1007/s12035-021-02505-8
AnnaMaria Maraschi 1 , Valentina Gumina 1 , Jessica Dragotto 2 , Claudia Colombrita 1 , Miguel Mompeán 3 , Emanuele Buratti 4 , Vincenzo Silani 1, 5, 6 , Marco Feligioni 2, 7 , Antonia Ratti 1, 8
Affiliation  

The nuclear RNA-binding protein TDP-43 forms abnormal cytoplasmic aggregates in the brains of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients and several molecular mechanisms promoting TDP-43 cytoplasmic mislocalization and aggregation have been proposed, including defects in nucleocytoplasmic transport, stress granules (SG) disassembly and post-translational modifications (PTM). SUMOylation is a PTM which regulates a variety of cellular processes and, similarly to ubiquitination, targets lysine residues. To investigate the possible regulatory effects of SUMOylation on TDP-43 activity and trafficking, we first assessed that TDP-43 is SUMO-conjugated in the nuclear compartment both covalently and non-covalently in the RRM1 domain at the predicted lysine 136 and SUMO-interacting motif (SIM, 106–110 residues), respectively. By using the SUMO-mutant TDP-43 K136R protein, we demonstrated that SUMOylation modifies TDP-43 splicing activity, specifically exon skipping, and influences its sub-cellular localization and recruitment to SG after oxidative stress. When promoting deSUMOylation by SENP1 enzyme over-expression or by treatment with the cell-permeable SENP1 peptide TS-1, the cytoplasmic localization of TDP-43 increased, depending on its SUMOylation. Moreover, deSUMOylation by TS-1 peptide favoured the formation of small cytoplasmic aggregates of the C-terminal TDP-43 fragment p35, still containing the SUMO lysine target 136, but had no effect on the already formed p25 aggregates. Our data suggest that TDP-43 can be post-translationally modified by SUMOylation which may regulate its splicing function and trafficking, indicating a novel and druggable mechanism to explore as its dysregulation may lead to TDP-43 pathological aggregation in ALS and FTD.



中文翻译:

SUMOylation 调节 TDP-43 剪接活性和核质分布

核 RNA 结合蛋白 TDP-43 在肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 患者的大脑中形成异常的细胞质聚集体,并且已经提出了几种促进 TDP-43 细胞质错误定位和聚集的分子机制,包括核质缺陷运输,应力颗粒(SG)拆卸和翻译后修饰(PTM)。SUMOylation 是一种 PTM,可调节多种细胞过程,并且与泛素化类似,靶向赖氨酸残基。为了研究 SUMO 化对 TDP-43 活性和贩运的可能调节作用,我们首先评估了 TDP-43 在 RRM1 结构域中在预测的赖氨酸 136 和 SUMO 相互作用的核隔室中以共价和非共价方式共轭结合基序(SIM,106-110 个残基),分别。通过使用 SUMO 突变体 TDP-43 K136R 蛋白,我们证明了 SUMO 化修饰 TDP-43 剪接活性,特别是外显子跳跃,并在氧化应激后影响其亚细胞定位和向 SG 的募集。当通过 SENP1 酶过表达或通过细胞可渗透的 SENP1 肽 TS-1 处理促进去SUMOylation 时,TDP-43 的细胞质定位增加,这取决于其 SUMOylation。此外,TS-1 肽的去SUMOylation 有利于C 末端TDP-43 片段p35 的小细胞质聚集体的形成,仍然含有SUMO 赖氨酸靶标136,但对已经形成的p25 聚集体没有影响。我们的数据表明 TDP-43 可以通过 SUMOylation 进行翻译后修饰,从而调节其剪接功能和运输,

更新日期:2021-08-19
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