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The Dsc complex and its role in Golgi quality control. Dsc 复合物及其在高尔基体质量控制中的作用。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1042/BST20230375
Yannick Weyer, David Teis

Membrane proteins play crucial roles in cellular functions. However, processes such as the insertion of membrane proteins into the endoplasmic reticulum (ER), their folding into native structures, the assembly of multi-subunit membrane protein complexes, and their targeting from the ER to specific organelles are prone to errors and have a relatively high failure rate. To prevent the accumulation of defective or orphaned membrane proteins, quality control mechanisms assess folding, quantity, and localization of these proteins. This quality control is vital for preserving organelle integrity and maintaining cellular health. In this mini-review, we will focus on how selective membrane protein quality control at the Golgi apparatus, particularly through the defective for SREBP cleavage (Dsc) ubiquitin ligase complex, detects orphaned proteins and prevents their mis-localization to other organelles.

膜蛋白在细胞功能中发挥着至关重要的作用。然而,膜蛋白插入内质网(ER)、折叠成原生结构、组装多亚基膜蛋白复合物以及从ER定向到特定细胞器等过程容易出错,失败率相对较高。为了防止有缺陷或无主膜蛋白的积累,质量控制机制要对这些蛋白的折叠、数量和定位进行评估。这种质量控制对于保持细胞器完整性和维持细胞健康至关重要。在这篇微型综述中,我们将重点讨论高尔基体上的选择性膜蛋白质量控制,特别是如何通过 SREBP 裂解缺陷(Dsc)泛素连接酶复合物检测孤岛蛋白并防止它们错误定位到其他细胞器。
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引用次数: 0
The dynamic regulatory network of phosphatidic acid metabolism: a spotlight on substrate cycling between phosphatidic acid and diacylglycerol. 磷脂酸代谢的动态调控网络:磷脂酸和二酰甘油之间的底物循环聚焦。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1042/BST20231511
Reika Tei

Mammalian cells utilize over 1000 different lipid species to maintain cell and organelle membrane properties, control cell signaling and processes, and store energy. Lipid synthesis and metabolism are mediated by highly interconnected and spatiotemporally regulated networks of lipid-metabolizing enzymes and supported by vesicle trafficking and lipid-transfer at membrane contact sites. However, the regulatory mechanisms that achieve lipid homeostasis are largely unknown. Phosphatidic acid (PA) serves as the central hub for phospholipid biosynthesis, acting as a key intermediate in both the Kennedy pathway and the CDP-DAG pathway. Additionally, PA is a potent signaling molecule involved in various cellular processes. This dual role of PA, both as a critical intermediate in lipid biosynthesis and as a significant signaling molecule, suggests that it is tightly regulated within cells. This minireview will summarize the functional diversity of PA molecules based on their acyl tail structures and subcellular localization, highlighting recent tools and findings that shed light on how the physical, chemical, and spatial properties of PA species contribute to their differential metabolic fates and functions. Dysfunctional effects of altered PA metabolism as well as the strategies cells employ to maintain PA regulation and homeostasis will also be discussed. Furthermore, this review will explore the differential regulation of PA metabolism across distinct subcellular membranes. Our recent proximity labeling studies highlight the possibility that substrate cycling between PA and DAG may be location-dependent and have functional significance in cell signaling and lipid homeostasis.

哺乳动物细胞利用 1000 多种不同的脂质来维持细胞和细胞器膜的特性、控制细胞信号传导和过程以及储存能量。脂质的合成和代谢由高度相互关联和时空调控的脂质代谢酶网络介导,并由膜接触点的囊泡贩运和脂质转移提供支持。然而,实现脂质平衡的调节机制在很大程度上还不为人知。磷脂酸(PA)是磷脂生物合成的中心枢纽,是肯尼迪途径和 CDP-DAG 途径的关键中间体。此外,PA 还是一种参与各种细胞过程的强效信号分子。PA 既是脂质生物合成的关键中间体,又是重要的信号分子,这种双重作用表明 PA 在细胞内受到严格调控。本小视图将根据 PA 分子的酰基尾部结构和亚细胞定位,总结 PA 分子的功能多样性,重点介绍最新的工具和发现,这些工具和发现揭示了 PA 物种的物理、化学和空间特性如何导致其不同的代谢命运和功能。本综述还将讨论 PA 代谢改变的功能障碍以及细胞为维持 PA 调节和平衡而采用的策略。此外,本综述还将探讨不同亚细胞膜对 PA 代谢的不同调控。我们最近的近距离标记研究强调了 PA 和 DAG 之间的底物循环可能是位置依赖性的,在细胞信号传导和脂质稳态中具有重要的功能意义。
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引用次数: 0
Phase separation and viral factories: unveiling the physical processes supporting RNA packaging in dsRNA viruses. 相分离和病毒工厂:揭示支持 dsRNA 病毒中 RNA 包装的物理过程。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1042/BST20231304
Cyril J Haller, Julia Acker, A Emilia Arguello, Alexander Borodavka

Understanding of the physicochemical properties and functions of biomolecular condensates has rapidly advanced over the past decade. More recently, many RNA viruses have been shown to form cytoplasmic replication factories, or viroplasms, via phase separation of their components, akin to numerous cellular membraneless organelles. Notably, diverse viruses from the Reoviridae family containing 10-12 segmented double-stranded RNA genomes induce the formation of viroplasms in infected cells. Little is known about the inner workings of these membraneless cytoplasmic inclusions and how they may support stoichiometric RNA assembly in viruses with segmented RNA genomes, raising questions about the roles of phase separation in coordinating viral genome packaging. Here, we discuss how the molecular composition of viroplasms determines their properties, highlighting the interplay between RNA structure, RNA remodelling, and condensate self-organisation. Advancements in RNA structural probing and theoretical modelling of condensates can reveal the mechanisms through which these ribonucleoprotein complexes support the selective enrichment and stoichiometric assembly of distinct viral RNAs.

在过去的十年中,人们对生物分子凝聚体的理化性质和功能的认识有了飞速的发展。最近的研究表明,许多 RNA 病毒通过其成分的相分离形成细胞质复制工厂或病毒体,类似于许多细胞膜无细胞器。值得注意的是,Reoviridae 家族的多种病毒含有 10-12 段双链 RNA 基因组,能诱导受感染细胞形成病毒浆。人们对这些无膜细胞质包涵体的内部运作以及它们如何支持具有分段 RNA 基因组的病毒中的 RNA 按比例组装知之甚少,这就提出了关于相分离在协调病毒基因组包装中的作用的问题。在这里,我们将讨论病毒增殖体的分子组成如何决定它们的特性,突出 RNA 结构、RNA 重塑和凝聚体自组织之间的相互作用。RNA 结构探测和凝集物理论建模的进步可以揭示这些核糖核蛋白复合物支持不同病毒 RNA 选择性富集和按比例组装的机制。
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引用次数: 0
The mRNA dynamics underpinning translational control mechanisms of Drosophila melanogaster oogenesis. 黑腹果蝇卵子发生过程中翻译控制机制的 mRNA 动力学基础
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1042/BST20231293
Livia V Bayer, Samantha N Milano, Diana P Bratu

Advances in the study of mRNAs have yielded major new insights into post-transcriptional control of gene expression. Focus on the spatial regulation of mRNAs in highly polarized cells has demonstrated that mRNAs translocate through cells as mRNA:protein granules (mRNPs). These complex self-assemblies containing nuclear and cytoplasmic proteins are fundamental to the coordinated translation throughout cellular development. Initial studies on translational control necessitated fixed tissue, but the last 30 years have sparked innovative live-cell studies in several cell types to deliver a far more nuanced picture of how mRNA-protein dynamics exert translational control. In this review, we weave together the events that underpin mRNA processes and showcase the pivotal studies that revealed how a multitude of protein factors engage with a transcript. We highlight a mRNA's ability to act as a 'super scaffold' to facilitate molecular condensate formation and further moderate translational control. We focus on the Drosophila melanogaster germline due to the extensive post-transcriptional regulation occurring during early oogenesis. The complexity of the spatio-temporal expression of maternal transcripts in egg chambers allows for the exploration of a wide range of mechanisms that are crucial to the life cycle of mRNAs.

mRNA 研究的进展为基因表达的转录后控制提供了重要的新见解。对高度极化细胞中 mRNA 空间调控的关注表明,mRNA 在细胞中以 mRNA:蛋白质颗粒(mRNPs)的形式进行转运。这些包含核蛋白和细胞质蛋白的复杂自组装是整个细胞发育过程中协调翻译的基础。最初的翻译控制研究必须使用固定组织,但过去 30 年来,在多种细胞类型中开展了创新性活细胞研究,对 mRNA 蛋白动态如何发挥翻译控制作用有了更细致入微的了解。在这篇综述中,我们将 mRNA 过程的基本事件编织在一起,并展示了揭示多种蛋白因子如何与转录本相互作用的关键研究。我们强调了 mRNA 作为 "超级支架 "的能力,以促进分子凝聚物的形成并进一步缓和翻译控制。我们的研究重点是黑腹果蝇生殖系,因为在早期卵子发生过程中会出现大量转录后调控。卵室中母体转录本的时空表达非常复杂,因此可以探索对 mRNA 生命周期至关重要的各种机制。
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引用次数: 0
Voltage-clamp fluorometry for advancing mechanistic understanding of ion channel mechanisms with a focus on acid-sensing ion channels. 电压钳荧光测定法促进对离子通道机制的机理认识,重点关注酸感应离子通道。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1042/BST20240165
Eleonora Centonze, Stephan Kellenberger

Voltage-clamp fluorometry (VCF) has revolutionized the study of ion channels by combining electrophysiology with fluorescence spectroscopy. VCF allows ion channel researchers to link dynamic structural changes, measured in real time, to function. Acid-sensing ion channels (ASICs) are Na+-permeable non-voltage-gated ion channels of the central and peripheral nervous system. They function as pH sensors, triggering neuronal excitation when pH decreases. Animal studies have shown the importance of ASICs for pain and fear sensation, learning, and neurodegeneration following ischaemic stroke. This review explores the technical bases and various developments of VCF, including fluorescence resonance energy transfer and the use of unnatural fluorescent amino acids. We provide an overview of VCF applications with a focus on ASICs, detailing how VCF has unveiled proton-induced conformational changes in key regions such as the acid pocket, wrist, and pore, crucial for understanding transitions between closed, open, and desensitized states.

电压钳荧光测定法(VCF)将电生理学与荧光光谱学相结合,彻底改变了离子通道研究。VCF 使离子通道研究人员能够将实时测量到的动态结构变化与功能联系起来。酸感应离子通道(ASIC)是中枢和外周神经系统中的Na+渗透性非电压门控离子通道。它们具有 pH 值传感器的功能,当 pH 值降低时会触发神经元兴奋。动物研究表明,ASIC 对缺血性中风后的疼痛和恐惧感觉、学习和神经变性具有重要作用。本综述探讨了 VCF 的技术基础和各种发展,包括荧光共振能量转移和非天然荧光氨基酸的使用。我们概述了 VCF 在 ASIC 上的应用,详细介绍了 VCF 如何揭示酸袋、腕和孔等关键区域中质子诱导的构象变化,这对于理解封闭、开放和脱敏状态之间的转变至关重要。
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引用次数: 0
Human E3 ubiquitin ligases: accelerators and brakes for SARS-CoV-2 infection. 人类 E3 泛素连接酶:SARS-CoV-2 感染的加速器和制动器。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1042/BST20230324
Jesse Pellman, Anna Goldstein, Mikołaj Słabicki

E3 ubiquitin ligases regulate the composition of the proteome. These enzymes mono- or poly-ubiquitinate their substrates, directly altering protein function or targeting proteins for degradation by the proteasome. In this review, we discuss the opposing roles of human E3 ligases as effectors and targets in the evolutionary battle between host and pathogen, specifically in the context of SARS-CoV-2 infection. Through complex effects on transcription, translation, and protein trafficking, human E3 ligases can either attenuate SARS-CoV-2 infection or become vulnerabilities that are exploited by the virus to suppress the host's antiviral defenses. For example, the human E3 ligase RNF185 regulates the stability of SARS-CoV-2 envelope protein through the ubiquitin-proteasome pathway, and depletion of RNF185 significantly increases SARS-CoV-2 viral titer (iScience (2023) 26, 106601). We highlight recent advances that identify functions for numerous human E3 ligases in the SARS-CoV-2 life cycle and we assess their potential as novel antiviral agents.

E3 泛素连接酶调节蛋白质组的组成。这些酶对它们的底物进行单泛素化或多泛素化,直接改变蛋白质的功能,或将蛋白质作为靶标由蛋白酶体降解。在这篇综述中,我们将讨论人类 E3 连接酶在宿主与病原体之间的进化之战中作为效应器和靶标的对立作用,特别是在 SARS-CoV-2 感染的背景下。通过对转录、翻译和蛋白质运输的复杂影响,人类 E3 连接酶既可以减轻 SARS-CoV-2 感染,也可以成为病毒利用来抑制宿主抗病毒防御的漏洞。例如,人类 E3 连接酶 RNF185 通过泛素-蛋白酶体途径调节 SARS-CoV-2 包膜蛋白的稳定性,RNF185 的缺失会显著增加 SARS-CoV-2 病毒的滴度(iScience (2023) 26, 106601)。我们重点介绍了最近的研究进展,这些进展确定了许多人类 E3 连接酶在 SARS-CoV-2 生命周期中的功能,我们还评估了它们作为新型抗病毒药物的潜力。
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引用次数: 0
Hetero-oligomeric interaction as a new regulatory mechanism for protein arginine methyltransferases. 异构体相互作用是蛋白质精氨酸甲基转移酶的一种新调控机制。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1042/BST20240242
Angela A Bae, Y George Zheng

Protein arginine methylation is a versatile post-translational protein modification that has notable cellular roles such as transcriptional activation or repression, cell signaling, cell cycle regulation, and DNA damage response. However, in spite of their extensive significance in the biological system, there is still a significant gap in understanding of the entire function of the protein arginine methyltransferases (PRMTs). It has been well-established that PRMTs form homo-oligomeric complexes to be catalytically active, but in recent years, several studies have showcased evidence that different members of PRMTs can have cross-talk with one another to form hetero-oligomeric complexes. Additionally, these heteromeric complexes have distinct roles separate from their homomeric counterparts. Here, we review and highlight the discovery of the heterodimerization of PRMTs and discuss the biological implications of these hetero-oligomeric interactions.

蛋白质精氨酸甲基化是一种多功能的蛋白质翻译后修饰,在细胞中具有显著的作用,如转录激活或抑制、细胞信号传导、细胞周期调控和 DNA 损伤反应。然而,尽管蛋白质精氨酸甲基转移酶(PRMTs)在生物系统中具有广泛的意义,但人们对其整个功能的了解仍有很大差距。人们已经确定,精氨酸甲基转移酶形成同源异构体复合物才能发挥催化活性,但近年来的一些研究表明,精氨酸甲基转移酶的不同成员之间可以相互交织,形成异源异构体复合物。此外,这些异构复合物具有不同于同构复合物的作用。在此,我们回顾并重点介绍 PRMTs 异源二聚体化的发现,并讨论这些异源同源异构体相互作用的生物学意义。
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引用次数: 0
Coordinating BNIP3/NIX-mediated mitophagy in space and time. 在空间和时间上协调 BNIP3/NIX 介导的有丝分裂
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1042/BST20221364
Natalie M Niemi, Jonathan R Friedman

Mitochondria maintain organellar homeostasis through multiple quality control pathways, including the clearance of defective or unwanted mitochondria by selective autophagy. This removal of mitochondria, mitophagy, is controlled in large part by the outer mitochondrial membrane mitophagy receptors BNIP3 and NIX. While it has long been appreciated that BNIP3 and NIX mediate mitophagy by controlling the recruitment of autophagic machinery to the mitochondrial surface, the requirement for the carefully controlled spatiotemporal regulation of receptor-mediated mitophagy has only recently come to light. Several new factors that regulate the BNIP3/NIX-mediated mitophagy pathway have emerged, and various loss-of-function cell and animal models have revealed the dire consequences of their dysregulation. In this mini-review, we discuss new insights into the mechanisms and roles of the regulation of BNIP3 and NIX and highlight questions that have emerged from the identification of these new regulators.

线粒体通过多种质量控制途径维持细胞器的平衡,包括通过选择性自噬清除有缺陷或不需要的线粒体。这种线粒体清除(线粒体吞噬)在很大程度上受线粒体外膜线粒体吞噬受体 BNIP3 和 NIX 的控制。长期以来,人们一直认为 BNIP3 和 NIX 通过控制线粒体表面自噬机制的招募来介导有丝分裂,但对受体介导的有丝分裂进行仔细的时空调控的要求直到最近才被发现。目前出现了几种调节 BNIP3/NIX 介导的有丝分裂途径的新因子,各种功能缺失细胞和动物模型揭示了它们失调的严重后果。在这篇微型综述中,我们将讨论对 BNIP3 和 NIX 的调控机制和作用的新认识,并重点讨论在发现这些新调控因子的过程中出现的问题。
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引用次数: 0
Progress towards understanding risk factor mechanisms in the development of autism spectrum disorders. 在了解自闭症谱系障碍发病的风险因素机制方面取得进展。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1042/BST20231004
Amelia Bryers, Cheryl A Hawkes, Edward Parkin, Neil Dawson

Autism spectrum disorders (ASD) are a heterogenous set of syndromes characterised by social impairment and cognitive symptoms. Currently, there are limited treatment options available to help people with ASD manage their symptoms. Understanding the biological mechanisms that result in ASD diagnosis and symptomatology is an essential step in developing new interventional strategies. Human genetic studies have identified common gene variants of small effect and rare risk genes and copy number variants (CNVs) that substantially increase the risk of developing ASD. Reverse translational studies using rodent models based on these genetic variants provide new insight into the biological basis of ASD. Here we review recent findings from three ASD associated CNV mouse models (16p11.2, 2p16.3 and 22q11.2 deletion) that show behavioural and cognitive phenotypes relevant to ASD. These models have identified disturbed excitation-inhibition neurotransmitter balance, evidenced by dysfunctional glutamate and GABA signalling, as a key aetiological mechanism. These models also provide emerging evidence for serotoninergic neurotransmitter system dysfunction, although more work is needed to clarify the nature of this. At the brain network level, prefrontal cortex (PFC) dysfunctional connectivity is also evident across these models, supporting disturbed PFC function as a key nexus in ASD aetiology. Overall, published data highlight the utility and valuable insight gained into ASD aetiology from preclinical CNV mouse models. These have identified key aetiological mechanisms that represent putative novel therapeutic targets for the treatment of ASD symptoms, making them useful translational models for future drug discovery, development and validation.

自闭症谱系障碍(ASD)是一种以社交障碍和认知症状为特征的异质性综合症。目前,可用于帮助自闭症患者控制症状的治疗方案非常有限。了解导致 ASD 诊断和症状的生物学机制是开发新干预策略的重要一步。人类基因研究已经发现了影响较小的常见基因变异和罕见的风险基因以及拷贝数变异(CNVs),它们大大增加了患 ASD 的风险。利用基于这些基因变异的啮齿类动物模型进行的反向转化研究为了解 ASD 的生物学基础提供了新的视角。在此,我们回顾了三个与 ASD 相关的 CNV 小鼠模型(16p11.2、2p16.3 和 22q11.2 缺失)的最新发现,这些模型显示出与 ASD 相关的行为和认知表型。这些模型发现,谷氨酸和 GABA 信号传导失调导致的兴奋-抑制神经递质平衡紊乱是一个关键的致病机制。这些模型还提供了血清素能神经递质系统功能失调的新证据,尽管还需要更多的工作来澄清其性质。在大脑网络层面,前额叶皮质(PFC)功能失调的连通性在这些模型中也很明显,这支持了前额叶皮质功能紊乱是 ASD 病因学中的一个关键环节。总之,已发表的数据凸显了临床前 CNV 小鼠模型在 ASD 病因学方面的实用性和宝贵价值。这些模型确定了治疗 ASD 症状的潜在新型治疗靶点的关键病因机制,使它们成为未来药物发现、开发和验证的有用转化模型。
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引用次数: 0
Suppression of double-stranded RNA sensing in cancer: molecular mechanisms and therapeutic potential. 抑制癌症中的双链 RNA 感知:分子机制和治疗潜力。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-30 DOI: 10.1042/BST20230727
Addison A Young, Holly E Bohlin, Jackson R Pierce, Kyle A Cottrell

Immunotherapy has emerged as a therapeutic option for many cancers. For some tumors, immune checkpoint inhibitors show great efficacy in promoting anti-tumor immunity. However, not all tumors respond to immunotherapies. These tumors often exhibit reduced inflammation and are resistant to checkpoint inhibitors. Therapies that turn these 'cold' tumors 'hot' could improve the efficacy and applicability of checkpoint inhibitors, and in some cases may be sufficient on their own to promote anti-tumor immunity. One strategy to accomplish this goal is to activate innate immunity pathways within the tumor. Here we describe how this can be accomplished by activating double-stranded RNA (dsRNA) sensors. These sensors evolved to detect and respond to dsRNAs arising from viral infection but can also be activated by endogenous dsRNAs. A set of proteins, referred to as suppressors of dsRNA sensing, are responsible for preventing sensing 'self' dsRNA and activating innate immunity pathways. The mechanism of action of these suppressors falls into three categories: (1) Suppressors that affect mature RNAs through editing, degradation, restructuring, or binding. (2) Suppressors that affect RNA processing. (3) Suppressors that affect RNA expression. In this review we highlight suppressors that function through each mechanism, provide examples of the effects of disrupting those suppressors in cancer cell lines and tumors, and discuss the therapeutic potential of targeting these proteins and pathways.

免疫疗法已成为许多癌症的治疗选择。对于某些肿瘤,免疫检查点抑制剂在促进抗肿瘤免疫方面显示出巨大疗效。然而,并非所有肿瘤都对免疫疗法有反应。这些肿瘤通常会表现出炎症减轻,并对检查点抑制剂产生抗药性。让这些 "冷 "肿瘤变 "热 "的疗法可以提高检查点抑制剂的疗效和适用性,在某些情况下,这种疗法本身就足以促进抗肿瘤免疫。实现这一目标的策略之一是激活肿瘤内的先天免疫途径。在这里,我们描述了如何通过激活双链 RNA(dsRNA)传感器来实现这一目标。这些传感器的进化是为了检测和响应病毒感染产生的 dsRNA,但也可被内源性 dsRNA 激活。一组被称为dsRNA感应抑制因子的蛋白质负责防止感应 "自身 "dsRNA并激活先天免疫途径。这些抑制因子的作用机制可分为三类:(1)通过编辑、降解、重组或结合影响成熟 RNA 的抑制因子。(2)影响 RNA 加工的抑制因子。(3)影响 RNA 表达的抑制因子。在这篇综述中,我们将重点介绍通过每种机制发挥作用的抑制因子,举例说明破坏这些抑制因子对癌细胞系和肿瘤的影响,并讨论针对这些蛋白和途径的治疗潜力。
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