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Inhibiting macrophage-derived lactate transport restores cGAS–STING signalling and enhances antitumour immunity in glioblastoma 抑制巨噬细胞来源的乳酸转运恢复cGAS-STING信号并增强胶质母细胞瘤的抗肿瘤免疫
IF 21.3 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2026-01-06 DOI: 10.1038/s41556-025-01839-y
Daqi Li, Gaoyuan Cui, Kailin Yang, Chenfei Lu, Yuhan Jiang, Le Zhang, Qiulian Wu, Deobrat Dixit, Zhe Zhu, Ryan C. Gimple, Danling Gu, Jiancheng Gao, Qiankun Lin, Hang Yu, Zhumei Shi, Yun Chen, Qianghu Wang, Guangfu Jin, Fan Lin, Junfei Shao, Qigang Zhou, Chong Liu, Chaojun Li, Yongping You, Nu Zhang, Junxia Zhang, Xu Qian, Qian Zhang, Jeremy N. Rich, Xiuxing Wang
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引用次数: 0
Mitochondrial asymmetry shifts T cell fate 线粒体不对称改变了T细胞的命运
IF 19.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2026-01-05 DOI: 10.1038/s41556-025-01841-4
Sarah May Russell, Mirren Charnley
The discovery that CD8+ T cells divide asymmetrically has generated considerable speculation regarding how such divisions regulate the fate of these cells. Excitingly, a recent study links the inheritance of a fate determinant to divergence in CD8+ T cell fate among the daughters of an asymmetric division.
CD8+ T细胞不对称分裂的发现引发了大量关于这种分裂如何调节这些细胞命运的猜测。令人兴奋的是,最近的一项研究将命运决定因素的遗传与不对称分裂子细胞中CD8+ T细胞命运的分化联系起来。
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引用次数: 0
T follicular helper cells transiently unlock a plasticity state in germinal centre B cells during the humoral immune response 在体液免疫应答过程中,T滤泡辅助细胞在生发中心B细胞中短暂地解锁一种可塑性状态。
IF 19.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-12-29 DOI: 10.1038/s41556-025-01833-4
Laurianne Scourzic, Franco Izzo, Matt Teater, Alexander P. Polyzos, Lucretia Cucereavii, Christopher R. Chin, Antonin Papin, Hugo B. Pinto, Coraline Mlynarczyk, Ioanna Tsialta, Min Xia, Abigail Lidoski, Robert M. Myers, Eva M. Israel, Leandro Venturutti, Simon P. Mackay, Kenneth B. Hoehn, Arthur I. Skoultchi, Wendy Béguelin, Matthias Stadtfeld, Zhengming Chen, Dan A. Landau, Ari M. Melnick, Effie Apostolou
During the germinal centre (GC) reaction, mature B cells undergo rapid and reversible phenotypic shifts that are essential for adaptive immunity. Here we report that GC B cells, unlike other mature B cells, transiently acquire a unique epigenetic plasticity, demonstrated by their enhanced capacity to reprogram to induced pluripotent stem cells. This plasticity depends on T follicular helper (TFH) cells and is not due to increased proliferation or MYC activation. Instead, it involves weakening of B-cell identity and derepression of stem and progenitor programs driven by NF-κB and other TFH-derived signals. Thus, physiological GC plasticity is tightly constrained by the affinity maturation process of positive selection. Loss of histone 1, a chromatin compaction regulator restricting the accessibility of embryonic stem cell programs, further enhances GC plasticity by bypassing this gatekeeping mechanism. Importantly, patients with B-cell lymphoma enriched for GC plasticity signatures had worse outcomes, suggesting that this mechanism may also contribute to lymphomagenesis. Scourzic et al. show that germinal centre B cells display an enhanced ability to reprogram to induced pluripotent stem cells compared to mature B cells. This ability indicates their higher plasticity level and is T follicular helper cell-dependent.
在生发中心(GC)反应过程中,成熟的B细胞经历快速可逆的表型变化,这对适应性免疫至关重要。在这里,我们报告GC B细胞,不像其他成熟的B细胞,暂时获得独特的表观遗传可塑性,证明了他们的能力增强重编程诱导多能干细胞。这种可塑性取决于T滤泡辅助细胞(TFH),而不是由于增殖增加或MYC激活。相反,它涉及到b细胞身份的减弱以及NF-κB和其他tfh衍生信号驱动的干细胞和祖细胞程序的抑制。因此,生理GC可塑性受到正选择亲和成熟过程的严格约束。组蛋白1(一种限制胚胎干细胞程序可及性的染色质压实调节因子)的缺失通过绕过这一守门机制进一步增强了GC的可塑性。重要的是,富含GC可塑性特征的b细胞淋巴瘤患者预后较差,表明该机制也可能有助于淋巴瘤的发生。
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引用次数: 0
Two distinct chromatin modules regulate proinflammatory gene expression 两种不同的染色质模块调节促炎基因的表达
IF 19.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-12-24 DOI: 10.1038/s41556-025-01819-2
Isabelle Seufert, Irene Gerosa, Vassiliki Varamogianni-Mamatsi, Anastasiya Vladimirova, Ezgi Sen, Stefanie Mantz, Anne Rademacher, Sabrina Schumacher, Panagiotis Liakopoulos, Petros Kolovos, Simon Anders, Jan-Philipp Mallm, Argyris Papantonis, Karsten Rippe
Gene activation and coregulation have been attributed to different mechanisms, such as enhancer–promoter interactions via chromatin looping or the accumulation of transcription factors into hubs or condensates. However, genome-wide studies exploring mechanistic differences in endogenous gene regulation in primary human cells are scarce. Here we dissect the proinflammatory gene expression programme induced by tumor necrosis factor (TNF) in human endothelial cells using sequencing- and imaging-based methods. Our findings, enabled by the co-accessibility analysis of deep-coverage single-cell chromatin accessibility data with our RWireX software, identified two distinct regulatory chromatin modules: autonomous links of co-accessibility (ACs) between separated sites and domains of contiguous co-accessibility (DCs) with increased local transcription factor binding. The TNF-dependent induction timing and strength as well as changes in transcriptional bursting kinetics differed for genes in the AC and DC modules, pointing to functionally distinct regulatory mechanisms. These findings provide a framework for understanding how cells achieve rapid and precise control of gene expression. Seufert et al. analyse chromatin accessibility to identify sites that open simultaneously in response to TNF. They discover two distinct types of co-accessible regulatory module for controlling the induction of proinflammatory gene expression.
基因激活和协同调节被归因于不同的机制,如通过染色质环增强子-启动子相互作用或转录因子积聚成枢纽或凝聚体。然而,探索人类原代细胞内源基因调控机制差异的全基因组研究很少。在这里,我们使用基于测序和成像的方法解剖由肿瘤坏死因子(TNF)在人内皮细胞中诱导的促炎基因表达程序。通过使用RWireX软件对深度覆盖的单细胞染色质可及性数据进行共可及性分析,我们的研究结果确定了两种不同的染色质调控模块:分离位点之间的共可及性(ACs)的自主链接和局部转录因子结合增加的连续共可及性(dc)结构域。AC和DC模块中基因的tnf依赖性诱导时间和强度以及转录破裂动力学的变化不同,表明功能上不同的调控机制。这些发现为理解细胞如何实现基因表达的快速和精确控制提供了一个框架。
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引用次数: 0
Interphase chromosome conformation is specified by distinct folding programmes inherited through mitotic chromosomes or the cytoplasm 间期染色体构象由有丝分裂染色体或细胞质遗传的不同折叠程序指定
IF 19.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-12-22 DOI: 10.1038/s41556-025-01828-1
Allana Schooley, Sergey V. Venev, Vasilisa Aksenova, Jesse W. Lehman, Emily Navarrete, Athma A. Pai, Mary Dasso, Job Dekker
Identity-specific chromosome conformation must be re-established at each cell division. To uncover how interphase folding is inherited, we developed an approach that segregates chromosome-intrinsic mechanisms from those propagated through the cytoplasm during G1 nuclear reassembly. Inducible degradation of proteins essential for the establishment of nucleocytoplasmic transport during mitotic exit enabled analysis of folding programmes with distinct modes of inheritance. Here we show that genome compartmentalization is driven entirely by chromosome-intrinsic factors. In addition to conventional compartmental segregation, the chromosome-intrinsic folding programme leads to prominent genome-scale microcompartmentalization of mitotically bookmarked cis-regulatory elements. The microcompartment conformation forms transiently during telophase and is subsequently modulated by a second folding programme inherited through the cytoplasm in early G1. This programme includes cohesin-mediated loop extrusion and factors involved in transcription and RNA processing. The combined and interdependent action of chromosome-intrinsic and cytoplasmic inherited folding programmes determines the interphase chromatin conformation as cells exit mitosis. Schooley et al. find that mitotically bookmarked loci drive a transient chromosome folding state during G1 entry that is subsequently modulated by factors inherited through the cytoplasm.
每次细胞分裂必须重新建立身份特异性染色体构象。为了揭示间期折叠是如何遗传的,我们开发了一种方法,将染色体内在机制与G1核重组期间通过细胞质传播的机制分离开来。在有丝分裂退出过程中,对核胞质运输的建立所必需的蛋白质的诱导降解使折叠程序具有不同的遗传模式。在这里,我们表明基因组区隔化完全是由染色体内在因素驱动的。除了传统的区室分离外,染色体固有的折叠程序导致有丝分裂书签顺式调控元件在基因组尺度上的显著微区室化。微室构象在末期短暂形成,随后在G1早期通过细胞质遗传的第二个折叠程序进行调节。该程序包括内聚蛋白介导的环挤压和参与转录和RNA加工的因素。当细胞退出有丝分裂时,染色体固有折叠程序和细胞质遗传折叠程序的相互作用决定了间期染色质的构象。
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引用次数: 0
Author Correction: E-type prostanoid receptor 4 drives resolution of intestinal inflammation by blocking epithelial necroptosis. 作者更正:e型前列腺素受体4通过阻断上皮坏死坏死驱动肠道炎症的消退。
IF 19.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-12-22 DOI: 10.1038/s41556-025-01863-y
Jay V Patankar, Tanja M Müller, Srinivas Kantham, Miguel Gonzalez Acera, Fabrizio Mascia, Kristina Scheibe, Mousumi Mahapatro, Christina Heichler, Yuqiang Yu, Wei Li, Barbara Ruder, Claudia Günther, Moritz Leppkes, Mano J Mathew, Stefan Wirtz, Clemens Neufert, Anja A Kühl, Jay Paquette, Kevan Jacobson, Raja Atreya, Sebastian Zundler, Markus F Neurath, Robert N Young, Christoph Becker
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引用次数: 0
Inheriting chromosome conformation 遗传染色体构象。
IF 19.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-12-22 DOI: 10.1038/s41556-025-01851-2
Kyle P. Eagen
Chromosomes unfold and refold each time cells divide. A study by Schooley et al. demonstrates that chromosome-intrinsic and cytoplasmic factors uniquely contribute to interphase chromosome structure, with new possibilities for how gene expression programs are passed from mother cells to daughter cells.
每次细胞分裂时,染色体展开并折叠。Schooley等人的一项研究表明,染色体内禀因子和细胞质因子对间期染色体结构有独特的贡献,这为基因表达程序如何从母细胞传递到子细胞提供了新的可能性。
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引用次数: 0
The G3BP stress-granule proteins reinforce the integrated stress response translation programme G3BP应激颗粒蛋白强化了综合应激反应翻译程序。
IF 19.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-12-19 DOI: 10.1038/s41556-025-01834-3
Jarrett Smith, David P. Bartel
When mammalian cells are exposed to stress, they co-ordinate the condensation of stress granules (SGs) through the action of proteins G3BP1 and G3BP2 (G3BPs) and, simultaneously, undergo a massive reduction in translation. Although SGs and G3BPs have been linked to this translation response, their overall impact has been unclear. Here we investigate the question of how, and indeed whether, G3BPs and SGs shape the stress translation response. We find that SGs are enriched for mRNAs that are resistant to the stress-induced translation shutdown. Although the accurate recruitment of these stress-resistant mRNAs does require the context of stress, a combination of optogenetic tools and spike-normalized ribosome profiling demonstrates that G3BPs and SGs are necessary and sufficient to both help prioritize the translation of their enriched mRNAs and help suppress cytosolic translation. Together, these results support a model in which G3BPs and SGs reinforce the stress translation programme by prioritizing the translation of their resident mRNAs. Smith and Bartel show that mRNA recruitment to stress granules imparts resistance to the integrated stress response translational shutdown.
当哺乳动物细胞暴露在压力下时,它们通过蛋白质G3BP1和G3BP2 (g3bp)的作用协调压力颗粒(SGs)的凝聚,同时经历大量的翻译减少。虽然SGs和g3bp与这种翻译反应有关,但它们的总体影响尚不清楚。在这里,我们研究了g3bp和SGs如何以及是否塑造了压力转换反应的问题。我们发现SGs富含抵抗应激诱导的翻译关闭的mrna。虽然这些抗逆性mrna的准确募集确实需要应激背景,但光遗传学工具和峰化核糖体分析的结合表明,g3bp和SGs是必要的,足以帮助优先翻译它们富集的mrna,并有助于抑制细胞质翻译。总之,这些结果支持一个模型,其中g3bp和SGs通过优先翻译其驻留mrna来加强应激翻译程序。
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引用次数: 0
Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment 自噬调节的线粒体遗传控制早期CD8+ T细胞命运承诺。
IF 19.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-12-19 DOI: 10.1038/s41556-025-01835-2
Mariana Borsa, Ana Victoria Lechuga-Vieco, Amir H. Kayvanjoo, Edward Jenkins, Yavuz Yazicioglu, Ewoud B. Compeer, Felix C. Richter, Simon Rapp, Robert Mitchell, Tom Youdale, Hien Bui, Emilia Kuuluvainen, Michael L. Dustin, Linda V. Sinclair, Pekka Katajisto, Anna Katharina Simon
T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8+ T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function. Borsa et al. show that asymmetric T cell division after activation requires autophagy to promote mitochondrial turnover, with T cells inheriting older mitochondria showing decreased degradation, reduced memory potential and altered metabolism.
T细胞免疫力随着年龄的增长而下降,伴随着自噬和不对称细胞分裂的下降。本研究表明,自噬调节CD8+ T细胞的线粒体遗传。利用小鼠模型对母细胞和子细胞中的线粒体进行序列标记,我们证明了自噬缺陷的T细胞不能清除有丝分裂前的旧线粒体,并对称地继承它们。相比之下,线粒体不对称分裂的自噬能力细胞产生具有不同命运的子细胞:那些保留旧线粒体的细胞表现出记忆潜力降低,而那些没有继承旧线粒体的细胞表现出更高的线粒体更新,寿命更长,并在同源抗原挑战下扩大。多组学分析表明,早期命运分化是由不同的代谢程序驱动的,在保留有丝分裂前线粒体的细胞中,单碳代谢被激活。这些发现促进了我们对T细胞多样性如何在分裂早期被印记的理解,并支持了调节T细胞功能的策略的发展。
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引用次数: 0
Permeability-driven pressure and cell proliferation control lumen morphogenesis in pancreatic organoids 胰腺类器官的通透性驱动压力和细胞增殖控制管腔形态发生。
IF 19.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-12-19 DOI: 10.1038/s41556-025-01832-5
Byung Ho Lee, Kana Fuji, Heike Petzold, Phil Seymour, Siham Yennek, Coline Schewin, Allison Lewis, Daniel Riveline, Tetsuya Hiraiwa, Masaki Sano, Anne Grapin-Botton
Lumen formation in organ epithelia involves processes such as polarization, secretion, exocytosis and contractility, but what controls lumen shape remains unclear. Here we study how lumina develop spherical or complex structures using pancreatic organoids. Combining computational phase-field modelling and experiments, we found that lumen morphology depends on the balance between cell cycle duration and lumen pressure, low pressure and high proliferation produce complex shapes. Manipulating proliferation and lumen pressure can alter or reverse lumen development both in silico and in vitro. Increasing epithelial permeability reduces lumen pressure, converting from spherical to complex lumina. During pancreas development, the epithelium is initially permeable and becomes sealed, experimentally increasing permeability at late stages impairs ductal morphogenesis. Overall, our work underscores how proliferation, pressure and permeability orchestrate lumen shape, offering insights for tissue engineering and cystic disease treatment. Using pancreatic organoids, Lee et al. show that the balance between epithelial tissue permeability-driven lumenal pressure and cell proliferation affects ductal morphogenesis.
器官上皮的管腔形成涉及极化、分泌、胞吐和收缩等过程,但控制管腔形状的因素尚不清楚。在这里,我们研究如何利用胰腺类器官形成球形或复杂的结构。结合计算相场模型和实验,我们发现管腔形态取决于细胞周期持续时间和管腔压力之间的平衡,低压和高增殖产生复杂的形状。控制增殖和管腔压力可以改变或逆转管腔的发展,无论是在硅和体外。增加上皮通透性降低管腔压力,从球形管腔转化为复杂管腔。在胰腺发育过程中,上皮最初是可渗透的,然后变得封闭,实验表明,晚期通透性的增加会损害导管的形态发生。总的来说,我们的工作强调了增殖、压力和渗透性如何协调管腔形状,为组织工程和囊性疾病治疗提供了见解。
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引用次数: 0
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Nature Cell Biology
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