The Role of E3 Ligases in Macrophage-mediated Inflammation  

E3连接酶在巨噬细胞介导的炎症中的作用

作　　者：JIN Jia-Bei GE Yi-Dong JIN Xiao-Feng 金加孛;葛一栋;金晓锋(宁波大学医学部生物化学与分子生物学系,浙江省病理生理学技术研究重点实验室,宁波315211)

机构地区：[1]Zhejiang Key Laboratory of Pathophysiology,Department of Biochemistry and Molecular Biology,Health Science Center,Ningbo University,Ningbo 315211,China

出　　处：《生物化学与生物物理进展》2024年第9期2037-2060,共24页Progress In Biochemistry and Biophysics

基　　金：宁波大学“医学部核心课程建设”项目;国家自然科学基金(32270821);宁波市自然科学基金(2021J065);宁波大学王宽诚基金和宁波大学大学生科研创新计划(SRIP)项目(2023SRIP1913)资助。

摘　　要：Macrophages,existed in almost all organs of the body,are responsible for detecting tissue injury,pathogens,playing a key role in host defense against a variety of invading pathogens triggering inflammatory responses.Emerging evidence suggests that macrophage-mediated immune responses are efficiently regulated by the ubiquitination modification,which is responsible for normal immune responses.However,numerous studies indicates that the aberrant activation or inhibition of macrophage-mediated immune responses occurs in inflammation,mainly caused by dysregulated ubiquitination modification due to E3 ubiquitin ligases mutations or abnormal expression.Notably,E3 ubiquitin ligases,responsible for recognizing the substrates,are key enzymes in the ubiquitin proteasome system(UPS)composed of ubiquitin(Ub),ubiquitin-activating E1 enzymes,ubiquitin-conjugating E2 enzymes,E3 ubiquitin ligases,26S proteasome,and deubiquitinating enzymes.Intriguingly,several E3 ubiquitin ligases are involved in the regulation of some common signal pathways in macrophage-mediated inflammation,including Toll-like receptors(TLRs),nucleotide-binding oligomerization domain(NOD)-like receptors(NLRs),RIG-I-like receptors(RLRs),C-type lectin receptors(CLRs)and the receptor for advanced glycation end products(RAGE).Herein,we summarized the physiological and pathological roles of E3 ligases in macrophage-mediated inflammation,as well as the inhibitors and agonists targeting E3 ligases in macrophage mediated inflammation,providing the new ideas for targeted therapies in macrophage-mediated inflammation caused aberrant function of E3 ligases.巨噬细胞几乎存在于人体的所有器官中,负责检测组织损伤、病原体,在宿主抵御各种入侵病原体引发炎症反应的过程中发挥关键作用。研究表明,巨噬细胞介导的免疫反应受到泛素-蛋白酶体系统(ubiquitin-proteasome system,UPS)的严格调控,其失调或异常激活可能是许多炎症发病机制的关键因素。负责识别底物的E3连接酶是UPS中的关键酶,它包含多种亚家族蛋白,参与调控巨噬细胞介导的炎症中的一些常见信号通路,如核苷酸结合寡聚化结构域样受体(nucleotide-binding oligomerization domain-like receptors,NLRs)、维甲酸诱导基因I样受体家族(retinoic acid-inducible gene 1-like receptors,RLRs)和Toll样受体(Toll-like receptors,TLRs)。本文总结了巨噬细胞介导的炎症相关E3连接酶的最新研究进展,并讨论了E3与其底物结合导致NLRs/RLRs/TLRs信号转导异常激活或失活的一些潜在机制。此外,还探讨了针对E3连接酶在巨噬细胞介导的炎症中作用的相关抑制剂和激动剂,展望了针对巨噬细胞介导的炎症中异常E3连接酶的靶向疗法的未来前景。

关 键 词：E3 ligases MACROPHAGE NLRs/RLRs/TLRs targeted therapies 

分 类 号：Q7[生物学—分子生物学] R737.33[医药卫生—肿瘤]