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The ATP-driven extractor ATAD1/Msp1 proof-reads protein translocation into mitochondria ATP驱动的提取器ATAD1/Msp1校对蛋白质转运到线粒体的过程
IF 19 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-01 DOI: 10.1016/j.tcb.2024.07.007

The accumulation of translocation intermediates in the mitochondrial import machinery threatens cellular fitness and is associated with cancer and neurodegeneration. A recent study by Weidberg and colleagues identifies ATAD1 as an ATP-driven extraction machine on the mitochondrial surface that pulls precursors into the cytosol to prevent clogging of mitochondrial import pores.

线粒体导入机制中转运中间体的积累会威胁细胞的健康,并与癌症和神经变性有关。Weidberg 及其同事最近的一项研究发现,ATAD1 是线粒体表面由 ATP 驱动的提取机器,它能将前体拉入细胞质,防止线粒体导入孔堵塞。
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引用次数: 0
Cancer takes many paths through G1/S. 癌症在G1/S有很多途径。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-01 Epub Date: 2023-11-10 DOI: 10.1016/j.tcb.2023.10.007
Erik S Knudsen, Agnieszka K Witkiewicz, Seth M Rubin

In the commonly accepted paradigm for control of the mammalian cell cycle, sequential cyclin-dependent kinase (CDK) and cyclin activities drive the orderly transition from G1 to S phase. However, recent studies using different technological approaches and examining a broad range of cancer cell types are challenging this established paradigm. An alternative model is evolving in which cell cycles utilize different drivers and take different trajectories through the G1/S transition. We are discovering that cancer cells in particular can adapt their drivers and trajectories, which has important implications for antiproliferative therapies. These studies have helped to refine an understanding of how CDK inhibition impinges on proliferation and have significance for understanding fundamental features of cell biology and cancer.

在普遍接受的哺乳动物细胞周期控制范式中,连续的周期蛋白依赖性激酶(CDK)和周期蛋白活性驱动从G1期到S期的有序过渡。然而,最近的研究使用不同的技术方法和检查广泛的癌细胞类型正在挑战这种既定的范式。另一种模型正在发展,其中细胞周期利用不同的驱动因素,并通过G1/S转变采取不同的轨迹。我们发现,特别是癌细胞可以调整它们的驱动因素和轨迹,这对抗增殖治疗具有重要意义。这些研究有助于完善对CDK抑制如何影响增殖的理解,并对理解细胞生物学和癌症的基本特征具有重要意义。
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引用次数: 0
Accessible high-speed image-activated cell sorting. 无障碍高速图像激活细胞分拣。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-01 Epub Date: 2024-05-23 DOI: 10.1016/j.tcb.2024.04.007
Terra M Kuhn, Malte Paulsen, Sara Cuylen-Haering

Over the past six decades, fluorescence-activated cell sorting (FACS) has become an essential technology for basic and clinical research by enabling the isolation of cells of interest in high throughput. Recent technological advancements have started a new era of flow cytometry. By combining the spatial resolution of microscopy with high-speed cell sorting, new instruments allow cell sorting based on simple image-derived parameters or sophisticated image analysis algorithms, thereby greatly expanding the scope of applications. In this review, we discuss the systems that are commercially available or have been described in enough methodological and engineering detail to allow their replication. We summarize their strengths and limitations and highlight applications that have the potential to transform various fields in basic life science research and clinical settings.

在过去的六十年里,荧光激活细胞分拣(FACS)通过高通量分离感兴趣的细胞,已成为基础和临床研究的一项重要技术。最近的技术进步开启了流式细胞仪的新时代。通过将显微镜的空间分辨率与高速细胞分拣相结合,新仪器可根据简单的图像衍生参数或复杂的图像分析算法进行细胞分拣,从而大大扩展了应用范围。在这篇综述中,我们将讨论市场上已有的系统,或在方法和工程方面有足够详细描述的系统,以便进行复制。我们总结了它们的优势和局限性,并重点介绍了有可能改变基础生命科学研究和临床环境中各个领域的应用。
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引用次数: 0
Copper and iron orchestrate cell-state transitions in cancer and immunity. 铜和铁协调癌症和免疫中的细胞状态转变
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-29 DOI: 10.1016/j.tcb.2024.07.005
Sebastian Müller, Tatiana Cañeque, Stéphanie Solier, Raphaël Rodriguez

Whereas genetic mutations can alter cell properties, nongenetic mechanisms can drive rapid and reversible adaptations to changes in their physical environment, a phenomenon termed 'cell-state transition'. Metals, in particular copper and iron, have been shown to be rate-limiting catalysts of cell-state transitions controlling key chemical reactions in mitochondria and the cell nucleus, which govern metabolic and epigenetic changes underlying the acquisition of distinct cell phenotypes. Acquisition of a distinct cell identity, independently of genetic alterations, is an underlying phenomenon of various biological processes, including development, inflammation, erythropoiesis, aging, and cancer. Here, mechanisms that have been uncovered related to the role of these metals in the regulation of cell plasticity are described, illustrating how copper and iron can be exploited for therapeutic intervention.

基因突变可以改变细胞特性,而非遗传机制则可以推动细胞快速、可逆地适应物理环境的变化,这种现象被称为 "细胞状态转换"。金属,尤其是铜和铁,已被证明是细胞状态转换的限速催化剂,控制着线粒体和细胞核中的关键化学反应,而线粒体和细胞核中的关键化学反应又控制着新陈代谢和表观遗传学的变化,是获得独特细胞表型的基础。独立于基因改变的独特细胞特性的获得是包括发育、炎症、红细胞生成、衰老和癌症在内的各种生物过程的基本现象。本文介绍了已发现的与这些金属在细胞可塑性调控中的作用有关的机制,说明了如何利用铜和铁进行治疗干预。
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引用次数: 0
Lipids and chromatin: a tale of intriguing connections shaping genomic landscapes. 脂质和染色质:塑造基因组景观的奇妙联系。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-25 DOI: 10.1016/j.tcb.2024.06.004
Maria Laura Sosa Ponce, Jennifer A Cobb, Vanina Zaremberg

Recent studies in yeast reveal an intricate interplay between nuclear envelope (NE) architecture and lipid metabolism, and between lipid signaling and both epigenome and genome integrity. In this review, we highlight the reciprocal connection between lipids and histone modifications, which enable metabolic reprogramming in response to nutrients. The endoplasmic reticulum (ER)-NE regulates the compartmentalization and temporal availability of epigenetic metabolites and its lipid composition also impacts nuclear processes, such as transcriptional silencing and the DNA damage response (DDR). We also discuss recent work providing mechanistic insight into lipid droplet (LD) formation and sterols in the nucleus, and the collective data showing Opi1 as a central factor in both membrane sensing and transcriptional regulation of lipid-chromatin interrelated processes.

最近的酵母研究揭示了核包膜(NE)结构与脂质代谢之间以及脂质信号转导与表观基因组和基因组完整性之间错综复杂的相互作用。在这篇综述中,我们将重点介绍脂质与组蛋白修饰之间的相互联系,这种联系能使代谢重编程对营养物质做出响应。内质网(ER)-NE 调节着表观遗传代谢产物的分区和时间可用性,其脂质组成也影响着转录沉默和 DNA 损伤应答(DDR)等核过程。我们还讨论了最近的工作,这些工作提供了对细胞核中脂滴(LD)形成和固醇的机理认识,以及显示 Opi1 是膜感应和转录调控脂质-染色质相互关联过程的核心因子的集体数据。
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引用次数: 0
Metabolism and HSC fate: what NADPH is made for. 新陈代谢与造血干细胞的命运:NADPH 的作用。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-24 DOI: 10.1016/j.tcb.2024.07.003
Claudia Morganti, Massimo Bonora, Keisuke Ito

Mitochondrial metabolism plays a central role in the regulation of hematopoietic stem cell (HSC) biology. Mitochondrial fatty acid oxidation (FAO) is pivotal in controlling HSC self-renewal and differentiation. Herein, we discuss recent evidence suggesting that NADPH generated in the mitochondria can influence the fate of HSCs. Although NADPH has multiple functions, HSCs show high levels of NADPH that are preferentially used for cholesterol biosynthesis. Endogenous cholesterol supports the biogenesis of extracellular vesicles (EVs), which are essential for maintaining HSC properties. We also highlight the significance of EVs in hematopoiesis through autocrine signaling. Elucidating the mitochondrial NADPH-cholesterol axis as part of the metabolic requirements of healthy HSCs will facilitate the development of new therapies for hematological disorders.

线粒体代谢在造血干细胞生物学调控中发挥着核心作用。线粒体脂肪酸氧化(FAO)是控制造血干细胞自我更新和分化的关键。在此,我们将讨论最近有证据表明线粒体中产生的NADPH可影响造血干细胞的命运。虽然 NADPH 具有多种功能,但造血干细胞显示出高水平的 NADPH,并优先用于胆固醇的生物合成。内源性胆固醇支持细胞外囊泡 (EV) 的生物生成,而细胞外囊泡对维持造血干细胞的特性至关重要。我们还强调了EVs通过自分泌信号在造血过程中的重要作用。阐明线粒体 NADPH 胆固醇轴是健康造血干细胞代谢需求的一部分,将有助于开发治疗血液病的新疗法。
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引用次数: 0
Smooth operator(s): dialing up and down neurotransmitter responses by G-protein regulators. 平稳的操作者:通过 G 蛋白调节器调节神经递质的反应。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-24 DOI: 10.1016/j.tcb.2024.07.002
Clementine E Philibert, Mikel Garcia-Marcos

G-protein-coupled receptors (GPCRs) are essential mediators of neuromodulation and prominent pharmacological targets. While activation of heterotrimeric G-proteins (Gαβɣ) by GPCRs is essential in this process, much less is known about the postreceptor mechanisms that influence G-protein activity. Neurons express G-protein regulators that shape the amplitude and kinetics of GPCR-mediated synaptic responses. Although many of these operate by directly altering how G-proteins handle guanine-nucleotides enzymatically, recent discoveries have revealed alternative mechanisms by which GPCR-stimulated G-protein responses are modulated at the synapse. In this review, we cover the molecular basis for, and consequences of, the action of two G-protein regulators that do not affect the enzymatic activity of G-proteins directly: Gα inhibitory interacting protein (GINIP), which binds active Gα subunits, and potassium channel tetramerization domain-containing 12 (KCTD12), which binds active Gβγ subunits.

G 蛋白偶联受体(GPCR)是神经调节的重要介质,也是重要的药理靶标。虽然 GPCR 对异源三聚体 G 蛋白(Gαβɣ)的激活在这一过程中至关重要,但人们对影响 G 蛋白活性的受体后机制知之甚少。神经元表达的 G 蛋白调节因子可影响 GPCR 介导的突触反应的幅度和动力学。虽然其中许多调节剂是通过直接改变 G 蛋白如何酶促处理鸟嘌呤核苷酸来发挥作用的,但最近的发现揭示了 GPCR 刺激的 G 蛋白反应在突触处受到调节的其他机制。在这篇综述中,我们将介绍两种不直接影响 G 蛋白酶活性的 G 蛋白调节剂作用的分子基础和后果:Gα抑制性相互作用蛋白(GINIP)能与活性Gα亚基结合,而含钾通道四聚体化结构域的12(KCTD12)能与活性Gβγ亚基结合。
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引用次数: 0
The epitranscriptome: reshaping the DNA damage response. 表转录组:重塑 DNA 损伤反应。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-23 DOI: 10.1016/j.tcb.2024.06.008
Vivian Kalamara, George A Garinis

Genomic instability poses a formidable threat to cellular vitality and wellbeing, prompting cells to deploy an intricate DNA damage response (DDR) mechanism. Recent evidence has suggested that RNA is intricately linked to the DDR by serving as template, scaffold, or regulator during the repair of DNA damage. Additionally, RNA molecules undergo modifications, contributing to the epitranscriptome, a dynamic regulatory layer influencing cellular responses to genotoxic stress. The intricate interplay between RNA and the DDR sheds new light on how the RNA epigenome contributes to the maintenance of genomic integrity and ultimately shapes the fate of damaged cells.

基因组的不稳定性对细胞的活力和健康构成了巨大威胁,促使细胞部署复杂的 DNA 损伤应答(DDR)机制。最近的证据表明,RNA 在 DNA 损伤修复过程中充当模板、支架或调节器的角色,与 DDR 密切相关。此外,RNA 分子会发生修饰,从而形成表转录组(epitranscriptome),这是一个影响细胞对基因毒性应激反应的动态调控层。RNA 与 DDR 之间错综复杂的相互作用为我们揭示了 RNA 表观基因组如何有助于维持基因组完整性并最终决定受损细胞的命运。
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引用次数: 0
ADAR1: from basic mechanisms to inhibitors. ADAR1:从基本机制到抑制剂。
IF 13 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-18 DOI: 10.1016/j.tcb.2024.06.006
Jan Rehwinkel, Parinaz Mehdipour

Adenosine deaminase acting on RNA 1 (ADAR1) converts adenosine to inosine in double-stranded RNA (dsRNA) molecules, a process known as A-to-I editing. ADAR1 deficiency in humans and mice results in profound inflammatory diseases characterised by the spontaneous induction of innate immunity. In cells lacking ADAR1, unedited RNAs activate RNA sensors. These include melanoma differentiation-associated gene 5 (MDA5) that induces the expression of cytokines, particularly type I interferons (IFNs), protein kinase R (PKR), oligoadenylate synthase (OAS), and Z-DNA/RNA binding protein 1 (ZBP1). Immunogenic RNAs 'defused' by ADAR1 may include transcripts from repetitive elements and other long duplex RNAs. Here, we review these recent fundamental discoveries and discuss implications for human diseases. Some tumours depend on ADAR1 to escape immune surveillance, opening the possibility of unleashing anticancer therapies with ADAR1 inhibitors.

作用于 RNA 的腺苷脱氨酶 1(ADAR1)可将双链 RNA(dsRNA)分子中的腺苷转化为肌苷,这一过程被称为 "A-to-I 编辑"。人类和小鼠缺乏 ADAR1 会导致以自发诱导先天性免疫为特征的严重炎症性疾病。在缺乏 ADAR1 的细胞中,未经编辑的 RNA 会激活 RNA 传感器。其中包括黑色素瘤分化相关基因 5(MDA5),它能诱导细胞因子(尤其是 I 型干扰素(IFN))、蛋白激酶 R(PKR)、寡腺苷酸合成酶(OAS)和 Z-DNA/RNA 结合蛋白 1(ZBP1)的表达。被 ADAR1 "化解 "的免疫原性 RNA 可能包括来自重复元件和其他长双链 RNA 的转录本。在此,我们回顾了这些最新的基本发现,并讨论了它们对人类疾病的影响。一些肿瘤依赖 ADAR1 逃避免疫监视,这为利用 ADAR1 抑制剂释放抗癌疗法提供了可能。
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引用次数: 0
Immune surveillance of senescence: potential application to age-related diseases 衰老的免疫监视:在老年相关疾病中的潜在应用
IF 19 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-17 DOI: 10.1016/j.tcb.2024.06.007

Several lines of evidence suggest that the age-dependent accumulation of senescent cells leads to chronic tissue microinflammation, which in turn contributes to age-related pathologies. In general, senescent cells can be eliminated by the host’s innate and adaptive immune surveillance system, including macrophages, NK cells, and T cells. Impaired immune surveillance leads to the accumulation of senescent cells and accelerates the aging process. Recently, senescent cells, like cancer cells, have been shown to express certain types of immune checkpoint proteins as well as non-classical immune-tolerant MHC variants, leading to immune escape from surveillance systems. Thus, immune checkpoint blockade (ICB) may be a promising strategy to enhance immune surveillance of senescence, leading to the amelioration of some age-related diseases and tissue dysfunction.

多种证据表明,衰老细胞的积累与年龄有关,会导致慢性组织微炎症,进而引发与年龄有关的病症。一般来说,衰老细胞可被宿主的先天性和适应性免疫监视系统(包括巨噬细胞、NK 细胞和 T 细胞)清除。免疫监视功能受损会导致衰老细胞的积累并加速衰老过程。最近的研究表明,衰老细胞和癌细胞一样,会表达某些类型的免疫检查点蛋白以及非经典的免疫耐受 MHC 变异体,从而导致免疫逃逸监视系统。因此,免疫检查点阻断(ICB)可能是一种很有前景的策略,可加强对衰老的免疫监视,从而改善一些与年龄有关的疾病和组织功能障碍。
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引用次数: 0
期刊
Trends in Cell Biology
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