Sato Yusuke, Terawaki Seigo, Oikawa Daisuke, Shimizu Kouhei, Okina Yoshinori, Ito Hidefumi, Tokunaga Fuminori
Center for Research on Green Sustainable Chemistry, Graduate School of Engineering, Tottori University, Tottori, Japan.
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Tottori, Japan.
Front Mol Biosci. 2023 Jan 16;10:1089213. doi: 10.3389/fmolb.2023.1089213. eCollection 2023.
In neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), the progressive accumulation of ubiquitin-positive cytoplasmic inclusions leads to proteinopathy and neurodegeneration. Along with the seven types of Lys-linked ubiquitin chains, the linear ubiquitin chain assembly complex (LUBAC)-mediated Met1-linked linear ubiquitin chain, which activates the canonical NF-κB pathway, is also involved in cytoplasmic inclusions of tau in AD and TAR DNA-binding protein 43 in ALS. Post-translational modifications, including heterologous ubiquitination, affect proteasomal and autophagic degradation, inflammatory responses, and neurodegeneration. Single nucleotide polymorphisms (SNPs) in and (which encodes HOIL-1L), components of LUBAC, were recently identified as genetic risk factors of AD. A structural biological simulation suggested that most of the SNPs that cause an amino acid replacement affect the structure and function of SHARPIN. Thus, the aberrant LUBAC activity is related to AD. Protein ubiquitination and ubiquitin-binding proteins, such as ubiquilin 2 and NEMO, facilitate liquid-liquid phase separation (LLPS), and linear ubiquitination seems to promote efficient LLPS. Therefore, the development of therapeutic approaches that target ubiquitination, such as proteolysis-targeting chimeras (PROTACs) and inhibitors of ubiquitin ligases, including LUBAC, is expected to be an additional effective strategy to treat neurodegenerative diseases.
在诸如阿尔茨海默病（AD）和肌萎缩侧索硬化症（ALS）等神经退行性疾病中，泛素阳性细胞质内含物的逐渐积累会导致蛋白病和神经退行性变。除了七种赖氨酸连接的泛素链外，激活经典核因子κB途径的线性泛素链组装复合物（LUBAC）介导的甲硫氨酸1连接的线性泛素链也参与了AD中tau蛋白的细胞质内含物以及ALS中TAR DNA结合蛋白43的形成。包括异源泛素化在内的翻译后修饰会影响蛋白酶体和自噬降解、炎症反应以及神经退行性变。LUBAC的组成成分 HOIP 和 HOIL-1L（由 HOIL-1L 编码）中的单核苷酸多态性（SNP）最近被确定为AD的遗传风险因素。一项结构生物学模拟表明，大多数导致氨基酸替换的 HOIP SNP会影响SHARPIN的结构和功能。因此，LUBAC活性异常与AD相关。蛋白质泛素化和泛素结合蛋白，如泛素连接蛋白2和NEMO，促进液-液相分离（LLPS），并且线性泛素化似乎能促进高效的LLPS。因此，开发针对泛素化的治疗方法，如蛋白酶靶向嵌合体（PROTAC）和包括LUBAC在内的泛素连接酶抑制剂，有望成为治疗神经退行性疾病的另一种有效策略。
