Molecular Cell最新文献

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Hypoxia-induced ribosomal RNA modifications in the peptidyl-transferase center contribute to anaerobic growth of bacteria 在肽基转移酶中心缺氧诱导的核糖体RNA修饰有助于细菌的厌氧生长

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2025-12-10 DOI: 10.1016/j.molcel.2025.11.018

Kensuke Ishiguro, Karin Midorikawa, Naoki Shigi, Satoshi Kimura, Aivar Liiv, Takeshi Yokoyama, Takuhiro Ito, Mikako Shirouzu, Jaanus Remme, Kenjyo Miyauchi, Tsutomu Suzuki

Ribosomal RNAs (rRNAs) contain various modifications that play critical roles in ribosome assembly and function. Here, we discovered two stereoselective methylations of the rRNA backbone in the peptidyl-transferase center (PTC) of the 50S subunit of Escherichia coli cultured under anaerobic conditions. Methylation occurs at carbon 5'(S) of ribose moieties of dihydrouridine at position 2449 (D5Sm2449) and 2'-O-metylcytidine at position 2498 (Cm5Sm2498). We identified the rlmX gene, encoding a cobalamin-dependent radical S-adenosylmethionine (SAM) methyltransferase responsible for these methylations. Intriguingly, D5Sm2449, Cm5Sm2498, and 5-hydroxycytidine (ho5C2501) in the PTC were elevated under anaerobic growth conditions. A double knockout strain lacking rlmX and rlhA (responsible for ho5C2501) impaired anaerobic growth. Biochemical studies showed that these rRNA modifications stimulate protein synthesis. The cryoelectron microscopy (cryo-EM) structure of the ribosome indicated that these hypoxia-induced modifications stabilize the P-site and the PTC. These findings demonstrate that ribosomes are activated by hypoxia-induced modifications to enhance translational capability and thereby survival, under anaerobic conditions.

核糖体rna （rrna）包含各种修饰，这些修饰在核糖体的组装和功能中起关键作用。在这里，我们发现在厌氧条件下培养的大肠杆菌50S亚基的肽基转移酶中心（PTC）的rRNA主干有两个立体选择性甲基化。甲基化发生在2449 （D5Sm2449）和2498 （Cm5Sm2498）位置的2'- o -甲基胞苷核糖部分的碳5'(S)处。我们确定了rlmX基因，编码负责这些甲基化的钴胺依赖性自由基s -腺苷甲硫氨酸（SAM）甲基转移酶。有趣的是，在厌氧生长条件下，PTC中的D5Sm2449， Cm5Sm2498和5-羟基胞苷（ho5C2501）升高。缺乏rlmX和rlhA（负责ho5C2501）的双敲除菌株会损害厌氧生长。生化研究表明，这些rRNA修饰刺激蛋白质合成。核糖体的冷冻电镜（cryo-EM）结构表明，这些缺氧诱导的修饰稳定了p位点和PTC。这些发现表明，在缺氧条件下，核糖体被缺氧诱导的修饰激活，以增强翻译能力，从而提高生存能力。

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引用次数: 0

HYPK promotes N-terminal protein acetylation through rapid ribosome exchange of NatA HYPK通过NatA的快速核糖体交换促进n端蛋白乙酰化

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2025-12-10 DOI: 10.1016/j.molcel.2025.11.017

Alfred M. Lentzsch, Ziyi Fan, Inayat U. Irshad, Edward P. O’Brien, Ajeet K. Sharma, Rachel Green, Shu-ou Shan

Numerous protein biogenesis factors cotranslationally facilitate the maturation of nascent proteins. Among them, N-terminal acetyltransferase A (NatA) acetylates the N terminus of ∼40% of the eukaryotic proteome. NatA is bound to Huntingtin-interacting protein K (HYPK), which inhibits NatA activity in vitro but enhances function in vivo. Here, kinetic and in-cell measurements resolve this paradox, showing that HYPK acts as a ribosome exchange factor for NatA. Without HYPK, hyper-tight ribosome binding prevents NatA from accessing additional ribosomes following each round of acetylation. HYPK accelerates NatA dissociation from the ribosome to license multiple turnovers, allowing a sub-stoichiometric level of this enzyme to globally acetylate the nascent proteome. Our results uncover a previously unidentified function of HYPK and demonstrate that a "Goldilocks" zone of ribosome interaction kinetics is required for cotranslational protein biogenesis machineries to act on all translating ribosomes in the cell.

许多蛋白质生物发生因子共同翻译促进新生蛋白质的成熟。其中，N端乙酰转移酶A （NatA）使约40%的真核蛋白质组的N端乙酰化。NatA与亨廷顿蛋白相互作用蛋白K （HYPK）结合，在体外抑制NatA活性，但在体内增强其功能。在这里，动力学和细胞内测量解决了这个悖论，表明HYPK作为NatA的核糖体交换因子。没有HYPK，超紧密核糖体结合阻止NatA在每一轮乙酰化后进入额外的核糖体。HYPK加速NatA与核糖体的分离，允许多次转换，允许这种酶的亚化学计量水平来全局乙酰化新生的蛋白质组。我们的研究结果揭示了HYPK先前未被发现的功能，并证明了协同翻译蛋白生物发生机制需要核糖体相互作用动力学的“金发姑娘”区才能作用于细胞中所有翻译核糖体。

引用次数: 0

Puromycin-sensitive aminopeptidase acts as an inhibitory auxiliary subunit of volume-regulated anion channels and regulates cGAMP transport 嘌呤霉素敏感氨基肽酶作为抑制辅助性亚基的容量调节阴离子通道和调节cGAMP运输

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2025-12-09 DOI: 10.1016/j.molcel.2025.11.014

Wenqiang Zheng, Tatsuya Hagino, Hao Wang, Henry Yi Cheng, Nicholas Koylass, Kevin Hong Chen, Haobo Wang, Sepehr Mani, Anish Kumar Mondal, Edward C. Twomey, Zhaozhu Qiu

Volume-regulated anion channels (VRACs) are large-pore channels expressed in most vertebrate cells and are critical for cell volume regulation and autocrine/paracrine signaling. Here, we identify the ubiquitously expressed puromycin-sensitive aminopeptidase (PSA) as a binding partner of the obligatory VRAC subunit SWELL1 (also known as LRRC8A) and determine the cryo-electron microscopy structure of the SWELL1-PSA complex. Three PSA molecules bind a single SWELL1 hexamer, coupling adjacent leucine-rich repeat (LRR) domains into local dimers. Functionally, PSA overexpression suppresses VRAC activation, whereas PSA deletion dramatically elevates basal channel activity. Notably, PSA’s modulation of VRACs requires physical binding but not aminopeptidase activity, indicating a structural mechanism. Our findings identify PSA as an auxiliary subunit of VRACs, highlight the role of intracellular LRR domains in allosteric channel gating, and suggest a strategy to tune VRAC function in diverse physiological contexts, including 2′3′-cyclic GMP-AMP (cGAMP) transport and downstream stimulator of interferon genes (STING) signaling.

体积调节阴离子通道（vrac）是在大多数脊椎动物细胞中表达的大孔通道，对细胞体积调节和自分泌/旁分泌信号传导至关重要。在这里，我们确定了无处不在表达的嘌呤霉素敏感氨基肽酶（PSA）作为VRAC必需亚基SWELL1（也称为LRRC8A）的结合伙伴，并确定了SWELL1-PSA复合物的低温电镜结构。三个PSA分子结合一个单一的SWELL1六聚体，将邻近的富含亮氨酸重复序列（LRR）结构域偶联成局部二聚体。功能上，PSA过表达抑制VRAC激活，而PSA缺失显著提高基础通道活性。值得注意的是，PSA对vrac的调节需要物理结合而不是氨基肽酶活性，这表明了一种结构机制。我们的研究结果确定了PSA是VRAC的辅助亚基，强调了细胞内LRR结构域在变构通道门控中的作用，并提出了在不同生理环境下调节VRAC功能的策略，包括2 ‘ 3 ’环GMP-AMP （cGAMP）运输和干扰素基因下游刺激因子（STING）信号传导。

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引用次数: 0

GCN2 monitors mRNA translation termination GCN2监测mRNA翻译终止

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2025-12-09 DOI: 10.1016/j.molcel.2025.11.015

Kailey Worner, Katharine R. Maschhoff, Gabrielle M. Schuh, Wenqian Hu

Controlling mRNA translation is critical for proper protein production. Although translation initiation and elongation regulations are becoming increasingly clear, whether and how translation termination is monitored remains poorly understood. Using an acute protein degradation system coupled with phenotypic rescue via ectopic expression, here we show that the impaired translation termination reaction leads to the rapid activation of GCN2, resulting in eIF2α phosphorylation and inhibition of translation initiation, which occurs prior to ribosome collisions. Ribosome profiling analyses reveal that GCN2 monitors terminating ribosomes and prevents ribosome collisions and translation readthrough when translation termination is compromised. This rapid activation of GCN2 by compromised translation termination occurs in both stem and somatic cells and in mouse and human cells. These results suggest a conserved surveillance mechanism for translation termination.

控制mRNA的翻译是正确的蛋白质生产的关键。虽然翻译起始和延伸的规定变得越来越清楚，是否以及如何监测翻译终止仍然知之甚少。利用急性蛋白质降解系统和异位表达的表型拯救，我们发现受损的翻译终止反应导致GCN2的快速激活，导致eIF2α磷酸化和翻译起始抑制，这发生在核糖体碰撞之前。核糖体分析表明，GCN2监测终止核糖体，并在翻译终止受损时防止核糖体碰撞和翻译读出。这种通过翻译终止受损的GCN2快速激活发生在干细胞和体细胞以及小鼠和人类细胞中。这些结果提示翻译终止存在一个保守的监视机制。

引用次数: 0

Hi-Coatis: Capturing the 3D interplay between transcription and chromatin architecture Hi-Coatis：捕捉转录和染色质结构之间的3D相互作用

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2025-12-04 DOI: 10.1016/j.molcel.2025.11.007

Meichen Wang, Hai-Qiang Dai

Conventional methods have failed to simultaneously integrate one-dimensional transcriptional studies with three-dimensional chromatin architecture. In this issue, Li et al.¹ present Hi-Coatis, an antibody- and probe-free approach that seamlessly maps active transcription-associated chromatin networks with high sensitivity and spatial resolution.

传统的方法未能同时整合一维转录研究与三维染色质结构。在这一期中，Li等人1提出了Hi-Coatis，这是一种无抗体和无探针的方法，可以无缝地绘制活性转录相关的染色质网络，具有高灵敏度和空间分辨率。

引用次数: 0

Two CTCF motifs impede cohesin-mediated DNA loop extrusion 两个CTCF基序阻碍黏结素介导的DNA环挤压

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2025-12-04 DOI: 10.1016/j.molcel.2025.11.001

Roman Barth, Richard Janissen, Laura Muras, Jaco van der Torre, Gabriele Litos, Eli van der Sluis, Ashmiani van den Berg, Iain F. Davidson, Jan-Michael Peters, Cees Dekker

Human cohesin extrudes DNA into loops and is positioned along the genome by stalling at the human CCCTC-binding factor (CTCF) upon encountering its N-terminal region (NTR). The mechanism underlying this stalling, however, is unresolved. Using single-molecule assays that monitor DNA loop extrusion (LE) in the presence of NTR fragments, we identify two amino acid motifs, YDF and KTYQR, which hinder LE. KTYQR is found to completely block LE activity, while YDF hinders cohesin from completing LE step cycles and converts cohesin into a unidirectional extruder by strengthening the affinity of STAG1 to DNA. We thus identify two distinct NTR motifs that stall LE via different yet synergistic mechanisms, highlighting the multifaceted ways employed by CTCF to modulate LE to shape and regulate genomes.

人黏结蛋白将DNA挤出成环，并在遇到人ccctc结合因子（CTCF）的n端区域（NTR）时停留在其上，沿基因组定位。然而，这种停滞背后的机制尚不清楚。利用单分子检测技术，在NTR片段存在的情况下监测DNA环挤压（LE），我们发现了两个氨基酸基序，YDF和KTYQR，它们阻碍了LE。发现KTYQR完全阻断LE活性，而YDF通过增强STAG1对DNA的亲和力，阻碍内聚蛋白完成LE阶跃循环，将内聚蛋白转化为单向挤出剂。因此，我们确定了两种不同的NTR基序，它们通过不同的协同机制阻止LE，突出了CTCF通过多方面的方式调节LE来塑造和调节基因组。

引用次数: 0

mTOR signaling during T cell activation promotes cytokine production in T cells through 3' UTR-mediated translation control. T细胞激活过程中的mTOR信号通过3' utr介导的翻译控制促进T细胞细胞因子的产生。

IF 16.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2025-12-04 DOI: 10.1016/j.molcel.2025.11.005

Anouk P Jurgens, Josephine Zwijnen, Antonia Bradarić, Floris P J van Alphen, Kaspar Bresser, Koos Rooijers, Arie J Hoogendijk, Branka Popović, Monika C Wolkers

T cells are key contributors to clearing our body of infected and malignant cells. During activation, T cells undergo profound translational alterations, and the evolutionarily and highly conserved kinase mammalian target of rapamycin (mTOR) is central in this process. It mediates T cell differentiation, homeostasis, and activation and promotes the production of pro-inflammatory cytokines. mTOR executes its translation activity through terminal oligopyrimidine (TOP) motifs located in the 5' untranslated region (5' UTR) of target genes. Here, we uncovered a distinct 3' UTR-mediated mechanism of mTOR signaling on cytokine production in T cells. Non-classical TOP motifs present in the cytokine 3' UTRs do not contribute to mTOR-mediated translation regulation. Rather, AU-rich elements (AREs) are required for mTOR-mediated cytokine production. Furthermore, we discovered that the RNA-binding protein DDX21 binds to 3' UTR AREs and confers mTOR-mediated translation control. In conclusion, we present a previously unappreciated ARE-dependent, 3' UTR-mediated mechanism that mTOR employs to regulate cytokine production.

T细胞是清除我们体内感染和恶性细胞的关键因素。在激活过程中，T细胞经历了深刻的翻译改变，而进化上高度保守的哺乳动物雷帕霉素靶蛋白激酶（mTOR）在这一过程中起着核心作用。它介导T细胞分化、稳态和激活，并促进促炎细胞因子的产生。mTOR通过位于靶基因5‘非翻译区（5’ UTR）的末端寡聚嘧啶（TOP）基序执行其翻译活性。在这里，我们发现了一个独特的3' utr介导的mTOR信号传导对T细胞细胞因子产生的机制。存在于细胞因子3′utr中的非经典TOP基序不参与mtor介导的翻译调控。相反，富含au的元素（AREs）是mtor介导的细胞因子产生所必需的。此外，我们发现rna结合蛋白DDX21与3' UTR区域结合，并赋予mtor介导的翻译控制。总之，我们提出了一种以前未被认识到的依赖于re的，3' utr介导的mTOR调节细胞因子产生的机制。

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引用次数: 0

A nucleotide regulates NR4A1 status in gastric cancer 一个核苷酸调节胃癌中NR4A1的状态

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2025-12-04 DOI: 10.1016/j.molcel.2025.11.012

Qi-Xiang Ma, Miao Yin, Qun-Ying Lei

How the oncogenic and tumor-suppressor roles of orphan nuclear receptor 4A1 (NR4A1) are balanced remains unclear. In this issue of Molecular Cell, Cai et al.¹ report that a pyrimidine metabolite—UMP—acts as an endogenous regulator of NR4A1 by directly binding to abrogate its suppressive effect on gastric cancer development.

孤儿核受体4A1 （NR4A1）的致癌和抑瘤作用是如何平衡的尚不清楚。Cai et al.1在本期Molecular Cell中报道了一种嘧啶代谢物- ump -通过直接结合NR4A1作为内源性调节剂，从而消除其对胃癌发展的抑制作用。

引用次数: 0

The landscape of regulated cell death: It’s all downhill from here 调控细胞死亡的图景：从这里开始，一切都在走下坡路

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2025-12-03 DOI: 10.1016/j.molcel.2025.11.013

Andreas Aufschnaiter, Teak-Jung Oh, Andrew Oberst

Cells can die via any of several forms of regulated cell death (RCD), including apoptosis, pyroptosis, and necroptosis. We now appreciate that there is substantial crosstalk between them, allowing for a high degree of plasticity downstream of cell death triggers. Understanding this is essential to delineate roles of RCD in development, homeostasis, tumor biology, and immunity; however, this crosstalk can make the fate of individual cells difficult to visualize. Here, we present a conceptual framework that builds on Waddington’s landscape model of lineage commitment. On the landscape of RCD, live cells begin atop a “mountain,” from which they roll down via “valleys” representing different cell death programs, potentially being diverted or even raised back to the summit by regulators of these processes. While acknowledging that, like any conceptual framework, this visualization is imperfect, we hope it presents a succinct approach to understand the complexities and interconnections of cell death regulation.

细胞可通过多种形式的细胞死亡（RCD）而死亡，包括凋亡、焦亡和坏死。我们现在认识到它们之间存在大量的串扰，允许细胞死亡触发器下游的高度可塑性。了解这一点对于描述RCD在发育、体内平衡、肿瘤生物学和免疫中的作用至关重要；然而，这种串扰会使单个细胞的命运难以可视化。在这里，我们提出了一个概念框架，它建立在Waddington的谱系承诺的景观模型之上。在RCD的图景中，活细胞从“山顶”开始，它们从代表不同细胞死亡程序的“山谷”滚下，可能被这些过程的监管者转移甚至抬升回山顶。虽然承认，像任何概念框架一样，这种可视化是不完美的，但我们希望它能提供一种简洁的方法来理解细胞死亡调控的复杂性和相互联系。

引用次数: 0

Rate-limiting enzymes in nucleotide metabolism synchronize nucleotide biosynthesis and chromatin formation 核苷酸代谢中的限速酶同步核苷酸生物合成和染色质形成

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2025-12-03 DOI: 10.1016/j.molcel.2025.11.009

Shashank Srivastava, Daniela Samaniego-Castruita, Shubhi Srivastava, Sakshi Khurana, Jalees Rehman, Vipul Shukla, Issam Ben-Sahra, Daniel R. Foltz

Chromatin formation requires both an adequate nucleotide supply and histone availability. Newly synthesized histones are escorted by histone chaperones that mediate their orderly transfer from ribosomes to DNA. While nucleotide and histone synthesis are the two major biosynthetic processes required for chromatin assembly, how these processes are coordinated remains unknown. Phosphoribosyl pyrophosphate synthetases (PRPSs), which catalyze the first and rate-limiting step in nucleotide biosynthesis, form a complex with PRPS-associated proteins (PRPSAPs). Using a rapid degron system in multiple human cell lines, we show that PRPS enzymes, together with PRPSAPs, play a key role in early histone maturation independent of their nucleotide biosynthetic function. Depletion of either PRPS1 or PRPSAP1 limits histone availability and disrupts chromatin assembly. These findings reveal a previously unrecognized synchrony between nucleotide metabolism and chromatin regulation, providing insight into how nucleotide production and histone deposition are coordinated.

染色质的形成既需要充足的核苷酸供应，也需要组蛋白的可用性。新合成的组蛋白由组蛋白伴侣护送，介导其从核糖体有序转移到DNA。虽然核苷酸和组蛋白合成是染色质组装所需的两个主要生物合成过程，但这些过程如何协调仍然未知。磷酸核糖基焦磷酸合成酶（prps）催化核苷酸生物合成的第一步和限速步骤，与prps相关蛋白（PRPSAPs）形成复合物。在多种人类细胞系中使用快速降解系统，我们发现PRPS酶和prpsap在独立于其核苷酸生物合成功能的早期组蛋白成熟中发挥关键作用。PRPS1或PRPSAP1的缺失限制了组蛋白的可用性并破坏了染色质组装。这些发现揭示了核苷酸代谢和染色质调节之间以前未被认识到的同步，为核苷酸产生和组蛋白沉积如何协调提供了见解。

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