Linear ubiquitination in immune and neurodegenerative diseases, and beyond
Linear ubiquitination in immune and neurodegenerative diseases, and beyond
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免疫和神经退行性疾病及其他疾病中的线性泛素化
DOI：
10.1042/bst20211078
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发表时间：
2022
影响因子：
3.9
通讯作者：
Ikeda Fumiyo
中科院分区：
文献类型：
--
作者：
Tokunaga Fuminori;Ikeda Fumiyo
泛素通过复杂的泛素代码调节生物学的许多方面。线性泛素链是一种非典型编码，形成独特的结构，远端泛素的C端尾部与近端泛素的N端Met1相连。迄今为止，LUBAC 是唯一已知的特异性生成线性泛素链的泛素连接酶复合物。 LUBAC 诱导的线性泛素链调节炎症反应、细胞死亡和免疫。转基因小鼠模型和细胞分析表明，LUBAC 还参与小鼠胚胎发育。 LUBAC 功能障碍与人类自身免疫性疾病、肌病和神经退行性疾病有关，但其潜在机制尚不清楚。在这篇综述中，我们重点关注线性泛素链和 LUBAC 在免疫和神经退行性疾病中的作用。我们进一步讨论了 LUBAC 抑制剂及其治疗这些疾病的潜力。
Ubiquitin regulates numerous aspects of biology via a complex ubiquitin code. The linear ubiquitin chain is an atypical code that forms a unique structure, with the C-terminal tail of the distal ubiquitin linked to the N-terminal Met1 of the proximal ubiquitin. Thus far, LUBAC is the only known ubiquitin ligase complex that specifically generates linear ubiquitin chains. LUBAC-induced linear ubiquitin chains regulate inflammatory responses, cell death and immunity. Genetically modified mouse models and cellular assays have revealed that LUBAC is also involved in embryonic development in mice. LUBAC dysfunction is associated with autoimmune diseases, myopathy, and neurodegenerative diseases in humans, but the underlying mechanisms are poorly understood. In this review, we focus on the roles of linear ubiquitin chains and LUBAC in immune and neurodegenerative diseases. We further discuss LUBAC inhibitors and their potential as therapeutics for these diseases.