摘要
HSCARG(也称为NmrA-like family redox sensor 1,NMRAL1)属于NmrA样蛋白家族.我们通过对HSCARG三维晶体结构的测定,首次证明了它是一种在哺乳动物细胞中广泛存在的NADP(H)传感器(sensor).对其功能的研究表明,HSCARG在调控细胞的氧化还原稳态、先天免疫、DNA损伤修复和癌症发生发展中发挥重要作用.HSCARG通过其N端的Rossmann折叠结构域选择性地结合还原型辅酶II(nicotinamide adenine dinucleaotide phosphate hydrogen,NADPH).当细胞内NADPH浓度降低时,HSCARG从同源二聚体转变为单体,并增强与其相互作用蛋白的相互作用.在细胞质中,HSCARG通过抑制细胞核转录因子-κB(nuclear factor-kappa B,NF-κB)和维甲酸诱导基因I受体(RIG-I like receptor,RLR)信号通路的活性来负调节先天免疫.此外,HSCARG通过抑制活性氧(reactive oxygen species,ROS)和一氧化氮(nitric oxide,NO)的产生来调节氧化还原平衡.持续的氧化应激导致HSCARG从细胞质转移到细胞核,在核内分别通过影响组蛋白H2A和增殖细胞核抗原(proliferating cell nuclear antigen,PCNA)的泛素化调节DNA损伤修复效率.总之,HSCARG作为细胞氧化还原状态与其他信号通路之间的联系,来精细地调控细胞对氧化还原变化的响应.该综述主要总结了我们在过去十五年对氧化还原细胞传感器HSCARG结构和功能的探索和认识.
HSCARG(also known as NmrA-like family redox sensor 1,NMRAL1)belongs to the NmrA-like protein family.Through the determination of the three-dimensional crystal structure of HSCARG,we demonstrated for the first time that it is a NADP(H)sensor widely present in mammalian cells.Our research on its functions indicates that HSCARG plays a pivotal role in regulating cellular redox homeostasis,innate immunity,DNA damage repair(DDR),and tumor development.HSCARG selectively binds to the reduced form of type Ⅱ coenzyme NADPH through its N-terminal Rossmann fold domain.When the intracellular concentration of NADPH decreases,HSCARG transitions from homodimer to monomer,enhancing its interactions with interacting proteins.In the cytoplasm,HSCARG negatively regulates innate immunity by inhibiting the activity of the NF-κB(nuclear factor-kappa B)and RLR(RIG-I-like receptor)signaling pathways.Furthermore,HSCARG regulates redox balance by suppressing the production of reactive oxygen species(ROS)and nitric oxide(NO).Persistent oxidative stress causes the cytoplasm-to-nucleus translocation of HSCARG,where it modulates the efficiency of DNA damage repair by affecting the ubiquitination of histone H2A and PCNA(proliferating cell nuclear antigen).In summary,HSCARG acts as a linkage between cellular redox status and other signaling pathways to finely tune the cellular response to redox changes.This review primarily summarizes our exploration and understanding of the structure and functions of the redox cellular sensor HSCARG over the past fifteen years.
作者
郑晓峰
ZHENG XiaoFeng(School of Life Sciences,Peking University,Beijing 100871,China)
出处
《中国科学:生命科学》
北大核心
2025年第5期948-956,共9页
Scientia Sinica(Vitae)
基金
国家自然科学基金(批准号:30930020,30670416)
国家重大科学研究计划(批准号:2010CB911800)
国家高技术研究发展计划(批准号:2006AA02A314)资助。
