内质网应激与脂类代谢

内质网应激激活的未折叠蛋白反应(unfolded protein response,UPR)是维持机体代谢平衡的重要信号通路。同时,内质网与脂类合成、转运和分解密切相关。近来研究发现UPR对脂类代谢具有调节作用。主要讨论内质网应激激活的UPR对脂类合成、转运和分解的影响及其机制。     

转录激活因子6：潜在的抗2 型糖尿病药物新靶点

真核细胞中的内质网是蛋白质合成、翻译和转运的场所,当内质网稳态被打破,出现蛋白质折叠障碍或错误折叠,并导致蛋白质过度积累时,便会引发内质网应激反应,即未折叠蛋白反应。大量的研究表明,内质网应激与2 型糖尿病的病理特征有一定的关系,而转录激活因子6 通路作为未折叠蛋白反应中3 条信号通路之一,调控着蛋白质的重折叠过程,对缓解内质网应激以及在糖脂代谢和胰岛素敏感性方面起着重要作用。简介内质网应激反应及相关信号通路和转录激活因子6,着重综述转录激活因子6 在肝脏糖脂代谢和胰岛素抵抗中的作用及相应机制,探讨其成为抗2 型糖尿病药物新靶点的可能性,为抗2 型糖尿病药物的研发提供新思路。     

非折叠蛋白反应——一条综合的细胞内信号通路

内质网(endoplasmic reticulum,ER)作为细胞中蛋白成熟的场所,可以很敏感的感受细胞内外环境的变化.当ER内环境改变,细胞就会激活信号应对这些改变,并且重新恢复折叠蛋白的环境.内质网的这种改变就是内质网应激(endophsmic reticulum stress,ERS),而对这种应激作出的反应就是非折叠蛋白反应[1](Unfolded Protein Response,UPR ).UPR至少引起了3种不同的信号通路,这些通路不仅调控分泌途径中大部分基因的表达,而且还广泛影响细胞的各个方面包括蛋白质、氨基酸和脂类的代谢.同时,这3务通路可以综合的调控细胞分泌器官的重塑并根据ERS重新调节细胞的生理活性.就UPR相关的感受器及其信号通路作简要的介绍.     

内质网应激与心血管疾病关系的研究进展

内质网是蛋白质折叠、转录后修饰和转运的重要细胞器,对维持细胞稳态具有重要作用。多种内外环境刺激能够引起内质网内错误折叠或未折叠蛋白的积累,即形成内质网应激。内质网应激激活未折叠蛋白反应(unfolded protein response,UPR),进而启动一系列下游信号以维持内质网稳态。但持续或过度的内质网应激激活的UPR最终导致细胞凋亡和疾病。近年来,大量研究证据表明,内质网应激参与多种心血管疾病(cardiovascular disease, CVD)的发生和发展,包括缺血性心脏病、糖尿病性心肌病、心力衰竭、动脉粥样硬化、血管钙化、高血压和主动脉瘤等,是治疗多种CVD的重要靶点。本文就内质网应激激活UPR在多种常见CVD中的调控机制以及内质网应激与CVD关系的研究进展作一简要综述。     

内质网应激与细胞自噬的关系

内质网应激(endoplasmic reticulum stress,ERS)是真核细胞普遍存在的应激–防御机制。ERS状态下,细胞会启动未折叠蛋白反应(unfolded protein response,UPR)增强对未折叠蛋白的折叠和对错误折叠蛋白的降解,以恢复内质网的正常生理功能。一些引发ERS的刺激也会诱发细胞自噬。自噬作为真核细胞保守的降解机制,可通过加快错误折叠蛋白的降解,降低ERS水平,是继UPR之外帮助内质网恢复稳态的另一重要角色。研究表明,ERS及其伴随的细胞自噬与很多疾病的发生发展密切相关。然而,ERS如何引发细胞自噬,自噬如何反馈调节ERS,UPR与细胞自噬如何关联,这些问题并未得到详细的探讨和阐释。因此,该文对ERS和细胞自噬的关系及其关联机制进行综述,以期为相关疾病发病机制的阐明和开发新的治疗策略提供依据。     

内质网应激诱导自噬的分子机制

在真核细胞中,内质网对蛋白质的折叠和运输至关重要,多种病理因素对内质网稳态的扰乱,可导致内质网腔中未折叠或错误折叠蛋白蓄积,即内质网应激(ERS)。细胞为此通过激活一种叫做未折叠蛋白反应(UPR)的防御反应来恢复内质网稳态。自噬是一种被描述为"自我吞食"的细胞代谢过程,其通过批量清除和降解未折叠蛋白以及破损细胞器在ERS时作为一种重要的保护机制。近年的研究显示这两个系统动态互联,且ERS可以通过多种方式诱导自噬的发生。在本文中,我们将总结目前关于ERS尤其是UPR诱导自噬的分子机制的相关知识,以进一步指导关于ERS与自噬关系的的研究。     

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的精密调控营造有利于其复制与增殖的细胞内环境。疱疹病毒是一类有囊膜的DNA病毒,在病毒复制过程中,其表面大量的糖基化囊膜蛋白的合成及成熟依赖于内质网,并由此诱发内质网应激。现将对疱疹病毒感染与内质网应激的最新研究进展做一总结归纳。     

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。     

内质网应激诱导的自噬在肝脏疾病中的研究进展

错误/未折叠蛋白的积累可导致内质网(endoplasmic reticulum, ER)结构和功能紊乱,从而诱发内质网应激(endoplasmic reticulum stress, ERS),激活未折叠蛋白反应(unfolded protein response, UPR)。UPR作为适应性机制可恢复早期的ERS,重建ER稳态;当UPR不足以缓解ERS时,会通过UPR介导的3个跨膜蛋白(IRE1α、PERK、ATF6)诱发细胞凋亡或自噬。自噬作为ERS的另一种保护性反应,可通过降解错误折叠蛋白和清除受损细胞器来减轻ERS。另外,自噬是ERS重要的下游事件并处于凋亡的上游,ERS介导的自噬可通过调节细胞凋亡发挥促凋亡或抗凋亡双重作用。ERS与自噬间的相互作用在酒精/非酒精性脂肪肝、肝纤维化、肝癌等多种肝脏疾病中扮演着重要角色,但二者在肝病发生发展过程中的具体机制尚不明确。因此,探讨ERS与自噬通过复杂的网络通路调控肝脏疾病的机制有助于改善相关肝脏疾病,这可能成为治疗肝病的有效靶点。     

Effect of the unfolded protein response on ER protein export: a potential new mechanism to relieve ER stress

The unfolded protein response (UPR) is an adaptive cellular response that aims to relieve endoplasmic reticulum (ER) stress via several mechanisms, including inhibition of protein synthesis and enhancement of protein folding and degradation. There is a controversy over the effect of the UPR on ER protein export. While some investigators suggested that ER export is inhibited during ER stress, others suggested the opposite. In this article, their conflicting studies are analyzed and compared in attempt to solve this controversy. The UPR appears indeed to enhance ER export, possibly via multiple mechanisms. However, another factor, which is the integrity of the folding machinery/environment inside ER, determines whether ER export will appear increased or decreased during experimentation. Also, different methods of stress induction appear to have different effects on ER export. Thus, improvement of ER export may represent a new mechanism by which the UPR alleviates ER stress. This may help researchers to understand how the UPR works inside cells and how to manipulate it to alter cell fate during stress, either to promote cell survival or death. This may open up new approaches for the treatment of ER stress-related diseases.     

HCV causes chronic endoplasmic reticulum stress leading to adaptation and interference with the unfolded protein response

Background

The endoplasmic reticulum (ER) is the cellular site for protein folding. ER stress occurs when protein folding capacity is exceeded. This stress induces a cyto-protective signaling cascades termed the unfolded protein response (UPR) aimed at restoring homeostasis. While acute ER stress is lethal, chronic sub-lethal ER stress causes cells to adapt by attenuation of UPR activation. Hepatitis C virus (HCV), a major human pathogen, was shown to cause ER stress, however it is unclear whether HCV induces chronic ER stress, and if so whether adaptation mechanisms are initiated. We wanted to characterize the kinetics of HCV-induced ER stress during infection and assess adaptation mechanisms and their significance.

Methods and Findings

The HuH7.5.1 cellular system and HCV-transgenic (HCV-Tg) mice were used to characterize HCV-induced ER stress/UPR pathway activation and adaptation. HCV induced a wave of acute ER stress peaking 2–5 days post-infection, which rapidly subsided thereafter. UPR pathways were activated including IRE1 and EIF2α phosphorylation, ATF6 cleavage and XBP-1 splicing. Downstream target genes including GADD34, ERdj4, p58ipk, ATF3 and ATF4 were upregulated. CHOP, a UPR regulated protein was activated and translocated to the nucleus. Remarkably, UPR activity did not return to baseline but remained elevated for up to 14 days post infection suggesting that chronic ER stress is induced. At this time, cells adapted to ER stress and were less responsive to further drug-induced ER stress. Similar results were obtained in HCV-Tg mice. Suppression of HCV by Interferon-α 2a treatment, restored UPR responsiveness to ER stress tolerant cells.

Conclusions

Our study shows, for the first time, that HCV induces adaptation to chronic ER stress which was reversed upon viral suppression. These finding represent a novel viral mechanism to manipulate cellular response pathways.     

Inhibition of fatty acid oxidation enhances oxidative protein folding and protects hepatocytes from endoplasmic reticulum stress

The unfolded protein response (UPR) signals protein misfolding in the endoplasmic reticulum (ER) to effect gene expression changes and restore ER homeostasis. Although many UPR-regulated genes encode ER protein processing factors, others, such as those encoding lipid catabolism enzymes, seem unrelated to ER function. It is not known whether UPR-mediated inhibition of fatty acid oxidation influences ER function or, if so, by what mechanism. Here we demonstrate that pharmacological or genetic inhibition of fatty acid oxidation renders liver cells partially resistant to ER stress-induced UPR activation both in vitro and in vivo. Reduced stress sensitivity appeared to be a consequence of increased cellular redox potential as judged by an elevated ratio of oxidized to reduced glutathione and enhanced oxidative folding in the ER. Accordingly, the ER folding benefit of inhibiting fatty acid (FA) oxidation could be phenocopied by manipulating glutathione recycling during ER stress. Conversely, preventing cellular hyperoxidation with N-acetyl cysteine partially negated the stress resistance provided by blocking FA oxidation. Our results suggest that ER stress can be ameliorated through alteration of the oxidizing environment within the ER lumen, and they provide a potential logic for the transient regulation of metabolic pathways by the UPR during stress.     

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.     

Unfolded protein response in chronic obstructive pulmonary disease: smoking, aging and disease: a SAD trifecta

Cigarette smoke (CS) is a risk factor for the development of chronic obstructive pulmonary disease (COPD). Oxidative stress is an immediate result of CS exposure and has the ability to modify cellular proteins. The endoplasmic reticulum (ER) is a compartment where early steps of synthesis and folding of membrane and secretory proteins takes place. Oxidative stress has been shown to interfere with protein folding in the ER and elicits the unfolded protein response (UPR). The UPR is a massive endoplasmic reticulum to the nucleus and the cellular kinase cascades signaling pathway. The UPR triggers a series of intracellular events that aim to help cells overcome the consequences of the stress or eliminate rogue cells by altering expression of genes involved in anti-oxidant defense, cell cycle progression, inflammation, and apoptosis. Recent data demonstrate that CS induces the UPR in vitro and in vivo. The timing of UPR induction in smokers and the mechanism of CS-induced UPR are areas of active investigation. The role of UPR in the protection of smoker's lungs from CS-induced oxidative stress, and its contribution to CS-induced apoptosis and inflammation, is beginning to emerge. This review discusses recent data about UPR in COPD and summarizes findings on UPR that have potential relevance to COPD.     

Endoplasmic reticulum stress and fungal pathogenesis

The gateway to the secretory pathway is the endoplasmic reticulum (ER), an organelle that is responsible for the accurate folding, post-translational modification and final assembly of up to a third of the cellular proteome. When secretion levels are high, errors in protein biogenesis can lead to the accumulation of abnormally folded proteins, which threaten ER homeostasis. The unfolded protein response (UPR) is an adaptive signaling pathway that counters a buildup in misfolded and unfolded proteins by increasing the expression of genes that support ER protein folding capacity. Fungi, like other eukaryotic cells that are specialized for secretion, rely upon the UPR to buffer ER stress caused by fluctuations in secretory demand. However, emerging evidence is also implicating the UPR as a central regulator of fungal pathogenesis. In this review, we discuss how diverse fungal pathogens have adapted ER stress response pathways to support the expression of virulence-related traits that are necessary in the host environment.     

The potential contribution of stromal cell-derived factor 2 (SDF2) in endoplasmic reticulum stress response in severe preeclampsia and labor-onset

Endoplasmic reticulum (ER) stress occurs when the protein folding machinery in the cell is unable to cope with newly synthesized proteins, which results in an accumulation of misfolded proteins in the ER lumen. In response, the cell activates a cellular signaling pathway known as the Unfolded Protein Response (UPR), aiming to restore cellular homeostasis. Activation and exacerbation of the UPR have been described in several human pathologies, including cancer and neurological disorders, and in some gestational diseases such as preeclampsia and gestational diabetes. This review explores the participation of stromal cell-derived factor 2 (SDF2) in UPR pathways, shows new information and discusses its exacerbation regarding protein expression in severe preeclampsia and labor, both of which are associated with ER stress.     

Oxidative protein folding and unfolded protein response elicit differing redox regulation in endoplasmic reticulum and cytosol of yeast

Oxidative protein folding can exceed the cellular secretion machinery, inducing the unfolded protein response (UPR). Sustained endoplasmic reticulum (ER) stress leads to cell stress and disease, as described for Alzheimer, Parkinson, and diabetes mellitus, among others. It is currently assumed that the redox state of the ER is optimally balanced for formation of disulfide bonds using glutathione as the main redox buffer and that UPR causes a reduction of this organelle. The direct effect of oxidative protein folding in the ER, however, has not yet been dissected from UPR regulation. To measure in vivo redox conditions in the ER and cytosol of the yeast model organism Pichia pastoris we targeted redox-sensitive roGFP variants to the respective organelles. Thereby, we clearly demonstrate that induction of the UPR causes reduction of the cytosol in addition to ER reduction. Similarly, a more reduced redox state of the cytosol, but not of the ER, is observed during oxidative protein folding in the ER without UPR induction, as demonstrated by overexpressing genes of disulfide bond-rich secretory proteins such as porcine trypsinogen or protein disulfide isomerase (PDI1) and ER oxidase (ERO1). Cytosolic reduction seems not to be caused by the action of glutathione reductase (GLR1) and could not be compensated for by overexpression of cytosolic glutathione peroxidase (GPX1). Overexpression of GPX1 and PDI1 oxidizes the ER and increases the secretion of correctly folded proteins, demonstrating that oxidative protein folding per se is enhanced by a more oxidized ER and is counterbalanced by a more reduced cytosol. As the total glutathione concentration of these strains does not change significantly, but the ratio of GSH to GSSG is altered, either transport or redox signaling between the glutathione pools of ER and cytosol is assumed. These data clearly demonstrate that protein folding and ER stress have a severe impact on the cytosolic redox balance, which may be a major factor during development of folding-related diseases.