Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Philips Institute for Oral Health Research, Virginia Commonwealth University, School of Dentistry, Richmond, VA, USA.
J Dent Res. 2021 Jan;100(1):10-20. doi: 10.1177/0022034520949486. Epub 2020 Aug 27.
Inflammation is triggered by stimulation of innate sensors that recognize pathogens, chemical and physical irritants, and damaged cells subsequently initiating a well-orchestrated adaptive immune response. Immune cell activation is a strictly regulated and self-resolving process supported by an array of negative feedback mechanisms to sustain tissue homeostasis. The disruption of these regulatory pathways forms the basis of chronic inflammatory diseases, including periodontitis. Ubiquitination, a covalent posttranslational modification of target proteins with ubiquitin, has a profound effect on the stability and activity of its substrates, thereby regulating the immune system at molecular and cellular levels. Through the cooperative actions of E3 ubiquitin ligases and deubiquitinases, ubiquitin modifications are implicated in several biological processes, including proteasomal degradation, transcriptional regulation, regulation of protein-protein interactions, endocytosis, autophagy, DNA repair, and cell cycle regulation. A20 (tumor necrosis factor α-induced protein 3 or TNFAIP3) is a ubiquitin-editing enzyme that mainly functions as an endogenous regulator of inflammation through termination of nuclear factor (NF)-κB activation as part of a negative feedback loop. A20 interacts with substrates that reside downstream of immune sensors, including Toll-like receptors, nucleotide-binding oligomerization domain-containing receptors, lymphocyte receptors, and cytokine receptors. Due to its pleiotropic functions as a ubiquitin binding protein, deubiquitinase and ubiquitin ligase, and its versatile role in various signaling pathways, aberrant A20 levels are associated with numerous conditions such as rheumatoid arthritis, diabetes, systemic lupus erythematosus, inflammatory bowel disease, psoriasis, Sjögren syndrome, coronary artery disease, multiple sclerosis, cystic fibrosis, asthma, cancer, neurological disorders, and aging-related sequelae. Similarly, A20 has recently been implicated as an essential regulator of inflammation in the oral cavity. This review presents information on the ubiquitin system and regulation of NF-κB by ubiquitination using A20 as a representative molecule and highlights how the dysregulation of this system can lead to several immune pathologies, including oral cavity-related disorders mainly focusing on periodontitis.
炎症是由先天传感器的刺激引发的，这些传感器可以识别病原体、化学和物理刺激物以及受损细胞，随后启动精心协调的适应性免疫反应。免疫细胞的激活是一个严格调控和自我消解的过程，受到一系列负反馈机制的支持，以维持组织的内稳态。这些调控途径的破坏是慢性炎症性疾病（包括牙周炎）的基础。泛素化是一种将泛素共价连接到靶蛋白上的翻译后修饰，它对其底物的稳定性和活性有深远的影响，从而在分子和细胞水平上调节免疫系统。通过 E3 泛素连接酶和去泛素酶的协同作用，泛素修饰参与了包括蛋白酶体降解、转录调控、蛋白质-蛋白质相互作用的调节、内吞作用、自噬、DNA 修复和细胞周期调控等多个生物学过程。A20（肿瘤坏死因子-α诱导蛋白 3 或 TNFAIP3）是一种泛素编辑酶，主要通过作为核因子（NF）-κB 激活的内源性调节剂来发挥作用，这是一个负反馈环的一部分。A20 与位于免疫传感器下游的底物相互作用，包括 Toll 样受体、核苷酸结合寡聚化结构域受体、淋巴细胞受体和细胞因子受体。由于其作为泛素结合蛋白、去泛素酶和泛素连接酶的多功能作用及其在各种信号通路中的多功能作用，异常的 A20 水平与许多疾病有关，如类风湿关节炎、糖尿病、系统性红斑狼疮、炎症性肠病、银屑病、干燥综合征、冠心病、多发性硬化症、囊性纤维化、哮喘、癌症、神经紊乱和与衰老相关的后遗症。同样，A20 最近被认为是口腔炎症的重要调节因子。本综述介绍了泛素系统的信息以及使用 A20 作为代表性分子的 NF-κB 的泛素化调控，并强调了该系统的失调如何导致包括口腔相关疾病（主要集中在牙周炎）在内的几种免疫病理。
