内质网应激偶联炎症反应与慢性病发病机制

内质网是合成细胞内分泌蛋白和膜蛋白并进行蛋白折叠的主要细胞器。新近研究证明,当内质网蛋白质合成与折叠的负担增加、非折叠或错误折叠蛋白质堆积,可激活内质网的几组特定信号转导通路,将这些应激信号传递到细胞浆和细胞核,引起未/错误折叠蛋白反应。这对维持细胞动态平衡和生物体的发育具有重要意义。更为重要的是,未/错误折叠蛋白反应能够与细胞内炎症反应信号转导通路偶联,是非感染性致病原引发炎症反应的主要原因。因此,内质网应激-未/错误折叠蛋白反应-炎症反应在特定的细胞发生偶联是许多炎症疾病的发病机制。本文综述该领域的研究进展,并介绍了内质网应激信号和炎症反应偶联参与一些慢性病发病的分子细胞机制。这些研究不仅加深人们对这些慢性病发病机制的了解,也有助于对调节内质网应激-炎症反应的药物的研发。     

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。     

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.     

The unfolded protein response and its role in intestinal homeostasis and inflammation

The unfolded protein response (UPR) is a signaling pathway from the endoplasmic reticulum (ER) to the nucleus that protects cells from the stress caused by misfolded or unfolded proteins [1, 2]. As such, ER stress is an ongoing challenge for all cells given the central biologic importance of secretion as part of normal physiologic functions. This is especially the case for cells that are highly dependent upon secretory function as part of their major duties. Within mucosal tissues, the intestinal epithelium is especially dependent upon an intact UPR for its normal activities [3]. This review will discuss the UPR and the special role that it provides in the functioning of the intestinal epithelium and, when dysfunctional, its implications for understanding mucosal homeostasis and intestinal inflammation, as occurs in inflammatory bowel disease (IBD).     

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。     

Calcium signaling at the endoplasmic reticulum: fine-tuning stress responses

Endoplasmic reticulum (ER) calcium signaling is implicated in a myriad of coordinated cellular processes. The ER calcium content is tightly regulated as it allows a favorable environment for protein folding, in addition to operate as a major reservoir for fast and specific release of calcium. Altered ER homeostasis impacts protein folding, activating the unfolded protein response (UPR) as a rescue mechanism to restore proteostasis. ER calcium release impacts mitochondrial metabolism and also fine-tunes the threshold to undergo apoptosis under chronic stress. The global coordination between UPR signaling and energetic demands takes place at mitochondrial associated membranes (MAMs), specialized subdomains mediating interorganelle communication. Here we discuss current models explaining the functional relationship between ER homeostasis and various cellular responses to coordinate proteostasis and metabolic maintenance.     

内质网应激响应在脂肪组织中的代谢调节作用

在真核细胞中,内质网是蛋白合成、加工及质量监控的关键细胞器,也是Ca2+储存及脂质合成的重要场所.细胞通过未折叠蛋白响应(unfolded protein response,UPR)感应外界不同刺激引发的内质网应激,在维持细胞功能稳态中发挥至关重要的作用.在哺乳动物中,三个位于内质网的跨膜蛋白——肌醇依赖酶la(ino...     

Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics

Endoplasmic reticulum (ER) stress activates an adaptive unfolded protein response (UPR) that facilitates cellular repair, however, under prolonged ER stress, the UPR can ultimately trigger apoptosis thereby terminating damaged cells. The molecular mechanisms responsible for execution of the cell death program are relatively well characterized, but the metabolic events taking place during the adaptive phase of ER stress remain largely undefined. Here we discuss emerging evidence regarding the metabolic changes that occur during the onset of ER stress and how ER influences mitochondrial function through mechanisms involving calcium transfer, thereby facilitating cellular adaptation. Finally, we highlight how dysregulation of ER-mitochondrial calcium homeostasis during prolonged ER stress is emerging as a novel mechanism implicated in the onset of metabolic disorders.     

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.     

Endoplasmic Reticulum Stress Interacts With Inflammation in Human Diseases

The endoplasmic reticulum (ER) is a critical organelle for normal cell function and homeostasis. Disturbance in the protein folding process in the ER, termed ER stress, leads to the activation of unfolded protein response (UPR) that encompasses a complex network of intracellular signaling pathways. The UPR can either restore ER homeostasis or activate pro‐apoptotic pathways depending on the type of insults, intensity and duration of the stress, and cell types. ER stress and the UPR have recently been linked to inflammation in a variety of human pathologies including autoimmune, infectious, neurodegenerative, and metabolic disorders. In the cell, ER stress and inflammatory signaling share extensive regulators and effectors in a broad spectrum of biological processes. In spite of different etiologies, the two signaling pathways have been shown to form a vicious cycle in exacerbating cellular dysfunction and causing apoptosis in many cells and tissues. However, the interaction between ER stress and inflammation in many of these diseases remains poorly understood. Further understanding of the biochemistry, cell biology, and physiology may enable the development of novel therapies that spontaneously target these pathogenic pathways. J. Cell. Physiol. 231: 288–294, 2016. © 2015 Wiley Periodicals, Inc.

     

Endoplasmic reticulum stress as a pro-fibrotic stimulus

Current evidence suggests a prominent role for endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in fibrotic conditions affecting a number of internal organs, including the lungs, liver, GI tract, kidney, and heart. ER stress enhances the susceptibility of structural cells, in most cases the epithelium, to pro-fibrotic stimuli. Studies suggest that ER stress facilitates fibrotic remodeling through activation of pro-apoptotic pathways, induction of epithelial–mesenchymal transition, and promotion of inflammatory responses. While genetic mutations that lead to ER stress underlie some cases of fibrosis, including lung fibrosis secondary to mutations in surfactant protein C (SFTPC), a variety of other factors can cause ER stress. These ER stress inducing factors include metabolic abnormalities, oxidative stress, viruses, and environmental exposures. Interestingly, the ability of the ER to maintain homeostasis under stress diminishes with age, potentially contributing to the fact that fibrotic disorders increase in incidence with aging. Taken together, underlying ER stress and UPR pathways are emerging as important determinants of fibrotic remodeling in different forms of tissue fibrosis. Further work is needed to better define the mechanisms by which ER stress facilitates progressive tissue fibrosis. In addition, it remains to be seen whether targeting ER stress and the UPR could have therapeutic benefit. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.