内质网应激反应分子机理研究进展

内质网应激是导致心脑组织缺血梗塞、神经退行性疾病等发生的重要环节 .目前发现同型半胱氨酸、氧化应激、钙代谢紊乱等都能引起内质网应激级联反应 ,表现为蛋白质合成暂停、内质网应激蛋白表达和细胞凋亡等 .这些表现包括在未折叠蛋白反应 (UPR)、整合应激反应 (ISR)和内质网相关性死亡 (ERAD)三个相互关联的动态过程中 ,每一过程的分子机理现已逐步被揭示 .作为细胞保护性应对机制的内质网应激体系一旦遭到破坏 ,细胞将不能合成应有的蛋白质 ,亦不能发挥正常的生理功能 ,甚至会出现细胞凋亡 .掌握内质网应激过程对进一步理解多种疾病的发生机理有十分重要的理论意义     

生命,死亡,未折叠蛋白反应与细胞凋亡

发生在细胞内的未折叠蛋白反应(unfolded protein response,UPR)是对内质网中未折叠蛋白聚积的应答。轻度内质网应激引起未折叠蛋白反应,出现新蛋白合成的暂停,使内质网有时间合成更多的分子伴侣来折叠蛋白质,从而使其功能恢复正常;严重或持续的内质网应激反应将导致细胞凋亡。     

内质网应激介导的细胞凋亡

内质网是细胞内重要的细胞器,内质网功能的损伤引起ER应激(ERS).内质网通过激活未折叠蛋白质反应(UPR)以保护由内质网应激所引起的细胞损伤,恢复细胞功能,包括暂停早期蛋白质合成、内质网分子伴侣和折叠酶的转录激活、内质网相关性降解(ERAD)的诱导.长期过强的内质网应激诱导内质网相关性细胞凋亡,清除受损细胞,包括内质网应激诱导CHOP/GADD153表达、JNK的激活以及caspase-12蛋白水解酶的活化等一系列生物学效应.     

内质网应激中Caspase-12的核心作用

内质网(ER)是细胞中一个重要的细胞器,主要功能是脂质的合成、储存以及蛋白质的折叠、加工等。因此,严格调控和维持内质网稳态是至关重要的。在缺氧、Ca~(2+)稳态发生紊乱或者在机体需求和蛋白质折叠装置能力不平衡等情况下都会引起内质网应激(ERS),此时内质网会启动了细胞的一个适应性反应,这种反应被称之为未折叠蛋白反应(UPR)。结果,定位于内质网的分子伴侣被诱导,蛋白质的合成会减缓,与此同时蛋白质的降解系统也会启动。如果内质网应激不能被缓解,细胞凋亡将随之发生。本综述分析了由内质网应激所引起的未折叠蛋白反应信号通道,以及Caspase-12在内质网凋亡途径中的核心作用。这为细胞凋亡的研究提供了一个新的角度,对肿瘤等疾病的治疗提供了一定的理论依据。     

疱疹病毒与内质网应激

内质网是分泌型蛋白和膜蛋白折叠及翻译后修饰的主要场所.病毒感染所引起的宿主细胞内环境的改变可使细胞或病毒的未折叠和/或错误折叠蛋白在内质网中大量聚集,使内质网处于生理功能紊乱的应激状态.为了缓解这种应激压力,细胞会启动未折叠蛋白反应(UPR),并通过一系列分子的信号转导维持内质网稳态;同时病毒也会通过对UPR的精密调控...     

嗜肺军团菌调控宿主非折叠蛋白反应的研究进展

内质网作为细胞内重要的细胞器之一,参与胞内蛋白的成熟及转运,其稳态与细胞的存活及免疫反应密切相关.非折叠蛋白反应是维持内质网稳态的重要机制之一,参与细胞的天然免疫反应,在宿主细胞抵抗病原体入侵中具有重要作用.嗜肺军团菌是一种革兰氏阴性致病菌,能够感染人体肺泡巨噬细胞引起严重肺炎,即军团菌病.在入侵宿主细胞后,嗜肺军团菌通过其Ⅳ型分泌系统将330多个效应蛋白转运至宿主细胞中,干扰宿主细胞的多种细胞进程,以形成其生存和复制所需的场所——含嗜肺军团菌囊泡(Legionella-containing vacuole, LCV).LCV的形成与宿主细胞的内质网密切相关.本文主要从嗜肺军团菌的致病机制、细胞非折叠蛋白反应及其与病原体的关系、军团菌对宿主细胞的非折叠蛋白反应的调控等方面进行综述,以期为揭示病原体与内质网应激之间的关系提供参考.     

内质网相关细胞器互作的研究进展

真核细胞中内质网是由片状和管状两种不同形态组成的连续的生物膜结构,参与细胞内蛋白质和脂质的合成以及钙离子稳态的调控等。内质网通过蛋白-蛋白及蛋白-脂质的相互作用与多种膜性细胞结构建立膜接触位点,进行物质的交换、信号转导、膜动态性调控等生理活动。内质网与膜性细胞结构互作的缺陷也会引发许多人类重大疾病。该文介绍了内质网与一系列膜性细胞结构接触位点形成的分子机制及其潜在功能。     

细胞内质网应激与糖脂代谢紊乱的机制关联

在真核细胞中,内质网是蛋白质合成、折叠、加工及其质量监控的重要场所。当内质网难以承担蛋白折叠的高负荷时则引发内质网应激(ER stress),激活细胞的未折叠蛋白响应(unfoldedprotein response,UPR)。细胞通过内质网跨膜蛋白ATF6、PERK和IRE1介导的三条极为关键的UPR信号通路,调控下游相关基因的表达,以增强内质网对蛋白折叠的处理能力。因此,UPR通路在细胞的稳态平衡中具有举足轻重的作用,而这一动态过程的调控对于维持机体的正常生理功能至关重要。近来大量研究表明,在哺乳动物中内质网应激与机体的营养感应和糖脂代谢的调控过程密切相关。在肝脏、脂肪、胰岛以及下丘脑等不同的组织器官中,内质网应激均影响代谢通路的调节机制,因此在糖脂代谢紊乱的发生发展中扮演重要的角色。综上所述,进一步深入了解内质网应激引发代谢异常的生理学机制,可以为肥胖、脂肪肝及2型糖尿病等相关代谢性疾病的防治提供新的潜在药物靶点和重要的理论线索。     

内质网应激与疾病

内质网是蛋白质合成与折叠、维持Ca²⁺动态平衡及合成脂类和固醇的场所。遗传或环境损伤引起内质网功能紊乱导致内质网应激,激活未折叠蛋白反应。未折叠蛋白反应是一种细胞自我保护性措施,但是内质网应激过强或持续时间过久可引起细胞凋亡。因此,内质网应激与众多人类疾病的发生发展密切相关。最近研究证明,癌症、炎症性疾病、代谢性疾病、骨质疏松症及神经退行性疾病等有内质网应激信号传递参与。然而内质网应激作为一个有效靶点参与各种疾病发挥作用的功能和机制仍然有待进一步研究。在近年来发表的文献基础上对内质网应激与疾病的关系,以及其可能的作用机制进行综述。     

内质网应激与心血管疾病

内质网存在于除哺乳动物成熟的红细胞外的各种真核细胞中,是蛋白质合成折叠、Ca2+储存和脂质合成的重要场所。多种因素刺激引起的内质网内稳态的失衡会导致未折叠蛋白、错误折叠蛋白堆积,即内质网应激。通过激活未折叠蛋白反应,细胞发生适应或凋亡。内质网应激参与了多种心血管疾病的病理过程,是研究心血管疾病发病机制和治疗干预的新途径。     

Unfolded Protein Response Signaling and Metabolic Diseases

The endoplasmic reticulum (ER) is a central organelle for protein biosynthesis, folding, and traffic. Perturbations in ER homeostasis create a condition termed ER stress and lead to activation of the complex signaling cascade called the unfolded protein response (UPR). Recent studies have documented that the UPR coordinates multiple signaling pathways and controls various physiologies in cells and the whole organism. Furthermore, unresolved ER stress has been implicated in a variety of metabolic disorders, such as obesity and type 2 diabetes. Therefore, intervening in ER stress and modulating signaling components of the UPR would provide promising therapeutics for the treatment of human metabolic diseases.     

Endoplasmic reticulum stress and lipids in health and diseases

The endoplasmic reticulum (ER) is a complex and dynamic organelle that regulates many cellular pathways, including protein synthesis, protein quality control, and lipid synthesis. When one or multiple ER roles are dysregulated and saturated, the ER enters a stress state, which, in turn, activates the highly conserved unfolded protein response (UPR). By sensing the accumulation of unfolded proteins or lipid bilayer stress (LBS) at the ER, the UPR triggers pathways to restore ER homeostasis and eventually induces apoptosis if the stress remains unresolved. In recent years, it has emerged that the UPR works intimately with other cellular pathways to maintain lipid homeostasis at the ER, and so does at cellular levels. Lipid distribution, along with lipid anabolism and catabolism, are tightly regulated, in part, by the ER. Dysfunctional and overwhelmed lipid-related pathways, independently or in combination with ER stress, can have reciprocal effects on other cellular functions, contributing to the development of diseases. In this review, we summarize the current understanding of the UPR in response to proteotoxic stress and LBS and the breadth of the functions mitigated by the UPR in different tissues and in the context of diseases.     

ER stress and the unfolded protein response

Conformational diseases are caused by mutations altering the folding pathway or final conformation of a protein. Many conformational diseases are caused by mutations in secretory proteins and reach from metabolic diseases, e.g. diabetes, to developmental and neurological diseases, e.g. Alzheimer's disease. Expression of mutant proteins disrupts protein folding in the endoplasmic reticulum (ER), causes ER stress, and activates a signaling network called the unfolded protein response (UPR). The UPR increases the biosynthetic capacity of the secretory pathway through upregulation of ER chaperone and foldase expression. In addition, the UPR decreases the biosynthetic burden of the secretory pathway by downregulating expression of genes encoding secreted proteins. Here we review our current understanding of how an unfolded protein signal is generated, sensed, transmitted across the ER membrane, and how downstream events in this stress response are regulated. We propose a model in which the activity of UPR signaling pathways reflects the biosynthetic activity of the ER. We summarize data that shows that this information is integrated into control of cellular events, which were previously not considered to be under control of ER signaling pathways, e.g. execution of differentiation and starvation programs.     

The impact of the unfolded protein response on human disease

A central function of the endoplasmic reticulum (ER) is to coordinate protein biosynthetic and secretory activities in the cell. Alterations in ER homeostasis cause accumulation of misfolded/unfolded proteins in the ER. To maintain ER homeostasis, eukaryotic cells have evolved the unfolded protein response (UPR), an essential adaptive intracellular signaling pathway that responds to metabolic, oxidative stress, and inflammatory response pathways. The UPR has been implicated in a variety of diseases including metabolic disease, neurodegenerative disease, inflammatory disease, and cancer. Signaling components of the UPR are emerging as potential targets for intervention and treatment of human disease.