Role of linear ubiquitination in inflammatory responses and tissue homeostasis
Role of linear ubiquitination in inflammatory responses and tissue homeostasis
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线性泛素化在炎症反应和组织稳态中的作用
DOI：
10.1093/intimm/dxac047
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发表时间：
2022
影响因子：
4.4
通讯作者：
Iwai Kazuhiro
中科院分区：
文献类型：
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作者：
Sasaki Katsuhiro;Iwai Kazuhiro
多聚泛素化是一种翻译后修饰，涉及广泛的免疫学事件，包括炎症反应、免疫细胞分化和炎性疾病的发展。多聚泛素化的多功能性是基于不同类型的泛素连接，其使得各种含有UBD（泛素结合域）的衔接蛋白能够缔合并诱导不同的生物输出。在免疫学领域专门研究了一种独特且非典型类型的多聚泛素链，其包含近端泛素部分的N-末端甲硫氨酸和远端泛素部分的C-末端甘氨酸之间的缀合，称为线性或M1-连接的泛素链，因为它不同于其他多聚泛素形式：线性遍在蛋白链主要由各种炎症刺激物（包括肿瘤坏死因子-α（TNF-α）和白细胞介素-1 β（IL-1β））产生，并作为瞬时和最佳信号转导的关键调节剂。此外，越来越多的证据表明，线性泛素链具有生理意义。线性泛素化的失调通过下调线性泛素依赖性核因子-κ B（NF-κB）信号转导和触发TNF-α诱导的细胞死亡触发慢性炎症和免疫缺陷，表明线性泛素化是组织特异性功能的稳态调节剂。在这篇综述中，我们集中在我们目前的理解的分子和细胞机制，线性泛素链控制炎症环境。此外，我们回顾了线性遍在蛋白化对T细胞发育、分化和功能的作用，从而深入了解其与维持免疫系统的直接关系。
Polyubiquitination is a post-translational modification involved in a wide range of immunological events, including inflammatory responses, immune cell differentiation, and development of inflammatory diseases. The versatile functions of polyubiquitination are based on different types of ubiquitin linkage, which enable various UBD (ubiquitin binding domain)-containing adaptor proteins to associate and induce distinct biological outputs. A unique and atypical type of polyubiquitin chain comprising a conjugation between the N-terminal methionine of the proximal ubiquitin moiety and the C-terminal glycine of the distal ubiquitin moiety, referred to as a linear or M1-linked ubiquitin chain, has been studied exclusively within the field of immunology because it is distinct from other polyubiquitin forms: linear ubiquitin chains are generated predominantly by various inflammatory stimulants, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and act as a critical modulator of transient and optimal signal transduction. Moreover, accumulating evidence suggests that linear ubiquitin chains are of physiological significance. Dysregulation of linear ubiquitination triggers chronic inflammation and immunodeficiency via downregulation of linear ubiquitin-dependent nuclear factor-kappa B (NF-κB) signaling and by triggering TNF-α-induced cell death, suggesting that linear ubiquitination is a homeostatic regulator of tissue-specific functions. In this review, we focus on our current understating of the molecular and cellular mechanisms by which linear ubiquitin chains control inflammatory environments. Furthermore, we review the role of linear ubiquitination on T cell development, differentiation, and function, thereby providing insight into its direct association with maintaining the immune system.