未折叠蛋白反应的信号转导

在内质网中,分泌性蛋白、跨膜蛋白和内质网驻留蛋白折叠成天然构象,经过修饰后,形成有活性的功能性蛋白质。如果蛋白质在内质网内的折叠受到抑制,造成未折叠蛋白聚集,将引起内质网应激。激活未折叠蛋白反应（unfolded protein response,UPR）,使蛋白质的生物合成减少,内质网的降解功能增强,从而降低内质网负担,维持细胞内的稳态。如果内质网应激持续存在,则可能诱发细胞凋亡。研究表明,未折叠蛋白反应能在多种肿瘤细胞中发生,并能促进肿瘤细胞的生长。本文对未折叠蛋白反应与肿瘤研究的最新进展进行综述。     

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。     

未折叠蛋白反应在神经退行性疾病中的作用

作为蛋白质分泌途径中蛋白质稳态的主要调节者,未折叠蛋白反应在正常和疾病中都起着至关重要的作用。本文简述了未折叠蛋白反应是否参与神经退行性疾病的发生发展。在许多体外和体内神经退行性病变模型中,未折叠蛋白反应的调节已显示出明显的应用前景。随着未折叠蛋白反应的研究不断深入,还出现了众多靶向未折叠蛋白反应的治疗策略。     

未折叠蛋白应答与疾病的关系

在Ca2 稳态平衡紊乱、葡萄糖饥饿、错误折叠蛋白质的表达、蛋白质糖基化的抑制或胆固醇合成超载等胁迫条件下,会导致内质网内积累大量的未折叠蛋白质,形成内质网应激(endoplasmic reticulum stress,ERS),对细胞产生根本性的危害。在应激条件下,内质网会产生未折叠蛋白应答(unfolded protein responseUPR),通过改变细胞的转录和翻译过程来缓解内质网应激,维持细胞功能;但是,如果细胞长时间处于UPR条件下,则会诱导细胞凋亡。     

microRNA调控未折叠蛋白反应的研究进展

microRNA(miRNA,miR)是一类非编码小单链RNA,可转录后抑制蛋白表达。未折叠蛋白反应(unfolded protein response,UPR)是在病理因素刺激下,由于错误蛋白聚集在内质网诱导细胞核减少蛋白合成以缓解内质网压力的保护措施。本文将概述microRNA调控未折叠蛋白反应的研究进展。     

未折叠蛋白反应—从内质网到细胞核的细胞内信号传导

在真核细胞中,内质网（ER）中未折叠蛋白聚集时,细胞为生存便会启动未折叠蛋白反应（unfolded protein response,UPR）,这种反应首先发现于酵母中,而其保守性使人们对哺乳动物细胞的RPR有了一定的认识。近年来发现哺乳动物细胞的RPR不仅参与蛋白质合成和分泌通路的调节,还与蛋白质翻译水平下调、细胞周期停滞、细胞凋亡及内质网相关性蛋白质降解（ER-associated degradation,ERAD）等生理过程有关。     

热激蛋白90抑制剂

分子伴侣热激蛋白90(heat-shock protein 90,Hsp90)在生物体内具有重要的生理功能,它在许多肿瘤细胞中表达增加。临床研究发现Hsp90抑制剂单一用药或者联合用药都具有较好的抗肿瘤效果,因此目前Hsp90被认为是癌症治疗一个非常有潜力的靶标。本文总结了Hsp90的结构功能、Hsp90抑制剂的作用机理以及Hsp90抑制剂的临床应用前景,希望为设计和开发新的Hsp90抑制剂提供一定的参考。     

未折叠蛋白反应在胰腺癌发生发展中的作用及意义

胰腺癌是一种致死率相当高的消化系统肿瘤，其起病隐蔽导致早期诊断困难。近期研究发现，内质网应激 (endoplasmic reticulum stress，ERS) 状态下的未折叠蛋白反应 (unfolded protein response，UPR) 通路的调节作用，对于胰腺癌发生发展至关重要。UPR通路伴侣蛋白 GRP78 抑制了胰腺导管腺癌 (pancreatic adenocarcinoma，PDAC)细胞的凋亡，并增强了其化学抗性和耐药性。而 UPR 途径及其调节因子对于血管内皮生长因子 (vascular endothelial growth factor，VEGF) 的调节作用，有助于胰腺癌抵抗缺血缺氧环境。尝试靶向 UPR 途径关键调节因子的药物来控制胰腺癌的研究，可以为胰腺癌的治疗开辟新的途径。本文通过对近年来 UPR 在胰腺癌发生发展中的作用及意义进行综述，希望为通过调控 UPR 通路作为针对治疗胰腺癌的关键过程的一种新型抗癌方法研究提供参考。     

未折叠蛋白反应在胰腺癌发生发展中的作用及意义

胰腺癌是一种致死率相当高的消化系统肿瘤,其起病隐蔽导致早期诊断困难。近期研究发现,内质网应激 (endoplasmic reticulum stress,ERS) 状态下的未折叠蛋白反应 (unfolded protein response,UPR) 通路的调节作用,对于胰腺癌发生发展至关重要。UPR通路伴侣蛋白 GRP78 抑制了胰腺导管腺癌 (pancreatic adenocarcinoma,PDAC)细胞的凋亡,并增强了其化学抗性和耐药性。而 UPR 途径及其调节因子对于血管内皮生长因子 (vascular endothelial growth factor,VEGF) 的调节作用,有助于胰腺癌抵抗缺血缺氧环境。尝试靶向 UPR 途径关键调节因子的药物来控制胰腺癌的研究,可以为胰腺癌的治疗开辟新的途径。本文通过对近年来 UPR 在胰腺癌发生发展中的作用及意义进行综述,希望为通过调控 UPR 通路作为针对治疗胰腺癌的关键过程的一种新型抗癌方法研究提供参考。     

Targeting the Unfolded Protein Response in Glioblastoma Cells with the Fusion Protein EGF-SubA

Rapidly growing tumors require efficient means to allow them to adapt to fluctuating microenvironments consisting of hypoxia, nutrient deprivation, and acidosis. The unfolded protein response (UPR) represents a defense mechanism allowing cells to respond to these adverse conditions. The chaperone protein GRP78 serves as a master UPR regulator that is aberrantly expressed in a variety of cancers, including glioma. Therefore, cancer cells may be particularly reliant upon the adaptive mechanisms offered by the UPR and targeting GRP78 may represent a unique therapeutic strategy. Here we report that diffuse expression of GRP78 protein is present in Grade III-IV, but not Grade I-II glioma. To determine the role GRP78 plays in glioblastoma tumorigenesis, we explored the anti-tumor activity of the novel fusion protein EGF-SubA, which combines EGF with the cytotoxin SubA that has been recently shown to selectively cleave GRP78. EGF-SubA demonstrated potent tumor-specific proteolytic activity and cytotoxicity in glioblastoma lines and potentiated the anti-tumor activity of both temozolomide and ionizing radiation. To determine if the tumor microenvironment influences EGF-SubA activity, we maintained cells in acidic conditions that led to both UPR activation and increased EGF-SubA induced cytotoxicity. EGF-SubA was well tolerated in mice and led to a significant tumor growth delay in a glioma xenograft mouse model. The UPR is emerging as an important adaptive pathway contributing to glioma tumorigenesis. Targeting its primary mediator, the chaperone protein GRP78, through specific, proteolytic cleavage with the immunotoxin EGF-SubA represents a novel and promising multi-targeted approach to cancer therapy.     

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.     

Antiviral Activity of a Small Molecule Deubiquitinase Inhibitor Occurs via Induction of the Unfolded Protein Response

Ubiquitin (Ub) is a vital regulatory component in various cellular processes, including cellular responses to viral infection. As obligate intracellular pathogens, viruses have the capacity to manipulate the ubiquitin (Ub) cycle to their advantage by encoding Ub-modifying proteins including deubiquitinases (DUBs). However, how cellular DUBs modulate specific viral infections, such as norovirus, is poorly understood. To examine the role of DUBs during norovirus infection, we used WP1130, a small molecule inhibitor of a subset of cellular DUBs. Replication of murine norovirus in murine macrophages and the human norovirus Norwalk virus in a replicon system were significantly inhibited by WP1130. Chemical proteomics identified the cellular DUB USP14 as a target of WP1130 in murine macrophages, and pharmacologic inhibition or siRNA-mediated knockdown of USP14 inhibited murine norovirus infection. USP14 is a proteasome-associated DUB that also binds to inositol-requiring enzyme 1 (IRE1), a critical mediator of the unfolded protein response (UPR). WP1130 treatment of murine macrophages did not alter proteasome activity but activated the X-box binding protein-1 (XBP-1) through an IRE1-dependent mechanism. In addition, WP1130 treatment or induction of the UPR also reduced infection of other RNA viruses including encephalomyocarditis virus, Sindbis virus, and La Crosse virus but not vesicular stomatitis virus. Pharmacologic inhibition of the IRE1 endonuclease activity partially rescued the antiviral effect of WP1130. Taken together, our studies support a model whereby induction of the UPR through cellular DUB inhibition blocks specific viral infections, and suggest that cellular DUBs and the UPR represent novel targets for future development of broad spectrum antiviral therapies.     

线粒体未折叠蛋白反应分子机制的研究进展

线粒体未折叠蛋白反应(UPR~(mt))作为新发现的细胞内应激机制,直接影响老化、神经退行性疾病、癌症等疾病的发生发展.UPR~(mt)是线粒体为了维持其内部蛋白质的平衡,启动由核DNA编码的线粒体热休克蛋白和蛋白酶等基因群转录活化程序的应激反应.深入探究UPR~(mt)的作用机制对阐明老化和线粒体相关疾病的发病机理具有指导意义.本文主要阐述了线粒体未折叠蛋白反应的诱导因素、线虫和哺乳动物细胞中最新的未折叠蛋白应激反应的信号传导通路、调控因子、具体作用机制以及线粒体未折叠蛋白反应与衰老、免疫等疾病的联系,旨在为这些疾病提供新的理论基础和治疗靶点.     

SirT3 Regulates the Mitochondrial Unfolded Protein Response

The mitochondria of cancer cells are characterized by elevated oxidative stress caused by reactive oxygen species (ROS). Such an elevation in ROS levels contributes to mitochondrial reprogramming and malignant transformation. However, high levels of ROS can cause irreversible damage to proteins, leading to their misfolding, mitochondrial stress, and ultimately cell death. Therefore, mechanisms to overcome mitochondrial stress are needed. The unfolded protein response (UPR) triggered by accumulation of misfolded proteins in the mitochondria (UPR^mt) has been reported recently. So far, the UPR^mt has been reported to involve the activation of CHOP and estrogen receptor alpha (ERα). The current study describes a novel role of the mitochondrial deacetylase SirT3 in the UPR^mt. Our data reveal that SirT3 acts to orchestrate two pathways, the antioxidant machinery and mitophagy. Inhibition of SirT3 in cells undergoing proteotoxic stress severely impairs the mitochondrial network and results in cellular death. These observations suggest that SirT3 acts to sort moderately stressed from irreversibly damaged organelles. Since SirT3 is reported to act as a tumor suppressor during transformation, our findings reveal a dual role of SirT3. This novel role of SirT3 in established tumors represents an essential mechanism of adaptation of cancer cells to proteotoxic and mitochondrial stress.     

未折叠蛋白响应的激活机制

未折叠蛋白在内质网（endoplasmic reticulum,ER）腔中累积造成ER应激，此时细胞启动未折叠蛋白响应（unfolded protein response,UPR）以恢复蛋白质稳态。目前已知有三种UPR感受器，即IRE1、PERK和ATF6，它们均为ER跨膜蛋白，在ER应激时被激活并启动下游UPR信号通路。虽然UPR感受器最早是在研究细胞如何应对ER应激时发现的，但它们如何感知ER应激至今未得到完满的回答。随着研究的深入，人们发现UPR的功能不仅限于维持蛋白质稳态，而UPR感受器也不是只对未折叠蛋白累积作出响应。本文对UPR的发现及其经典通路作一介绍，着重阐述目前已知的UPR感受器的激活机制，并就UPR和ER应激关系以及该领域存在的问题进行讨论。