神经损伤诱导蛋白1在诱导细胞质膜破裂中的作用  

A Role of Nerve Injury-induced Protein 1(NINJ1)in Inducing Plasma Membrane Rupture

作　　者：樊浩[1] 赵丹 焦放 FAN Hao;ZHAO Dan;JIAO Fang(School of Pharmacy,Jiangxi University of Chinese Medicine,Nanchang 330004,China;Laboratory of Soft Matter Physics,Institute of Physics,Chinese Academy of Sciences,Beijing 100190,China)

机构地区：[1]江西中医药大学药学院,南昌330004 [2]中国科学院物理研究所软物质物理实验室,北京100190

出　　处：《中国生物化学与分子生物学报》2024年第12期1659-1665,共7页Chinese Journal of Biochemistry and Molecular Biology

基　　金：国家自然科学基金项目(No.32371525,No.T2221001,No.92353304);江西省自然科学基金项目(No.5252101404)资助。

摘　　要：细胞质膜破裂(plasma membrane rupture,PMR)是细胞程序性死亡的最后一步,这一过程会将细胞内容物(包括促炎细胞因子和损伤相关分子模式(damage-associated molecular patterns,DAMPs)等)释放到细胞外环境,引发或放大炎症反应。最新研究发现神经损伤诱导蛋白1(nerve injury-induced protein 1,NINJ1)是多种程序性细胞死亡中质膜破裂(plasma membrane rupture,PMR)的关键介质。本综述结合最新研究成果,聚焦于NINJ1在细胞死亡方面的关键作用,探讨NINJ1的分子结构、功能及在炎症性疾病中作为治疗靶点的潜在应用。非激活态的NINJ1具有多个α-螺旋结构,包括两个跨膜α-螺旋结构及游离在胞外的N端(1-78,包含α-螺旋结构)结构域。当NINJ1被激发后能发生寡聚并使处于胞外的α-螺旋结构插入细胞膜,从而引发细胞质膜破裂。根据已解析的NINJ1激活态分子结构,已提出2种不同的NINJ1诱发细胞质膜破裂分子机制,一种是NINJ1形成环状或拉链结构,通过其内部亲水结构切割细胞膜,另一种NINJ1也形成环状结构,但其亲水区在环外会将NINJ1跟细胞膜一起切掉。同属Ninjurin家族的NINJ2与NINJ1在结构上高度相似,却不能介导质膜破裂,揭示细微的结构差异即可改变NINJ1的溶膜功能。通过阻止NINJ1介导的质膜破裂,可减轻炎症反应。未来的研究可能会集中在开发针对NINJ1的抑制剂,以期通过调控其功能来治疗相关的炎症性疾病。Plasma membrane rupture(PMR)is the terminal event in programmed cell death,leading to the release of cellular contents into the extracellular environment,including pro-inflammatory cytokines and damage-associated molecular patterns(DAMPs).This release plays a crucial role in triggering or amplifying the inflammatory response.Recent studies have identified nerve injury-induced protein 1(NINJ1)as a key mediator of PMR in several forms of programmed cell death.This review will examine the critical role of NINJ1 in cell death,considering recent research findings,and explore its molecular structure,function,and potential as a therapeutic target in inflammatory diseases.In its inactive state,NINJ1 contains multipleα-helical structures,including two transmembraneα-helices and a free extracellular N-terminal domain(residues 1-78)that also featuresα-helical regions.Upon activation,NINJ1 oligomerizes and its extracellularα-helices insert into the plasma membrane,initiating PMR.Two conflicting models of NINJ1-mediated PMR have been proposed based on cryo-EM resolved structures of activated NINJ1.One suggests that NINJ1 forms amphipathic filaments or pores with a hydrophilic conduit.In contrast,another model posits that NINJ1 forms membrane nanodiscs with a hydrophilic outer face,acting like cookie cutters to perforate cell membranes.Despite sharing significant structural similarity with NINJ1,NINJ2,another member of the ninjurin family,does not induce PMR,underscoring the functional impact of subtle structural variations.Inhibition of NINJ1-mediated PMR has been shown to reduce inflammatory responses,highlighting its potential as a therapeutic target.Future research may focus on developing NINJ1 inhibitors to modulate its activity for treating inflammation-related diseases.

关 键 词：神经损伤诱导蛋白1 细胞死亡 质膜破裂 

分 类 号：Q71[生物学—分子生物学]