Molecular Cell最新文献

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A Heavy Chain Reaction: Unraveling loop extrusion dynamics during VDJ recombination 重链式反应：VDJ复合过程中展开环挤压动力学

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2026-01-22 DOI: 10.1016/j.molcel.2025.12.021

Naiming Chen, Rushad Pavri

In this issue of Molecular Cell, Ollikainen et al. combine computational simulations with empirical data to reveal how the dynamics of chromatin loop extrusion at the immunoglobulin heavy chain locus enable comparable frequencies of VDJ recombination across megabases of chromatin.

在本期的《分子细胞》杂志上，Ollikainen等人将计算模拟与经验数据结合起来，揭示了免疫球蛋白重链位点染色质环挤压的动力学如何使染色质上的VDJ重组频率在大碱基上相当。

引用次数: 0

EGO complex at 20: The Rag GTPase-TORC1 nutrient-sensing blueprint 20岁时的EGO复合体：Rag GTPase-TORC1营养感应蓝图

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2026-01-22 DOI: 10.1016/j.molcel.2025.12.018

Claudio De Virgilio

引用次数: 0

Fin(e)-tuning ferroptosis 鳍(e)调优ferroptosis

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2026-01-22 DOI: 10.1016/j.molcel.2025.12.030

Krystina Julia Szylo, Scott James Dixon

引用次数: 0

PDCD5 promotes substrate release from the TRiC complex in cilia and flagella. PDCD5促进底物从纤毛和鞭毛的TRiC复合体中释放。

IF 16.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2026-01-22 Epub Date: 2026-01-07 DOI: 10.1016/j.molcel.2025.12.012

Huafang Wei, Qianqian Song, Liying Wang, Qiong Deng, Bingbing Wu, Yinghong Chen, Tingting Han, Yueshuai Guo, Zuyang Li, Fucheng Dong, Shuang Ma, Qiaoyu Zhao, Xiangyi Shi, Chen Pan, Wanying Jiang, Xiaofei Liu, Yingyu Chen, Renjie Jiao, Li Yuan, Chao Liu, Xuejiang Guo, Yao Cong, Wei Li

Approximately 10% of eukaryotic proteins are folded by the TRiC/CCT complex (TCP1-ring complex, also called CCT for cytosolic chaperonin containing TCP1), and only open-state TRiC can bind with programmed cell death 5 (PDCD5). However, the physiological role of the PDCD5-TRiC interaction remains elusive. Here, we show that PDCD5 is required for flagellum biogenesis and ciliogenesis and present the PDCD5-TRiC structures in their open states at near-atomic resolution. Mechanically, we find that PDCD5 promotes substrates release by competing with PhLP2A to interact with TRiC, and the depletion of PDCD5 traps flagellum- and cilium-associated proteins within TRiC, finally leading to malformed flagella of spermatids and cilia in mouse ciliated cells. Moreover, we demonstrate that the function of PDCD5 in flagellum biogenesis and ciliogenesis depends on the interaction with TRiC by its C terminus. These findings identify PDCD5 as a TRiC regulator to promote a subset of proteins release.

大约10%的真核蛋白被TRiC/CCT复合物（TCP1-环复合物，也称为CCT，含有TCP1的细胞质伴侣蛋白）折叠，只有开放状态的TRiC可以与程序性细胞死亡5 （PDCD5）结合。然而，PDCD5-TRiC相互作用的生理作用仍然难以捉摸。在这里，我们证明了PDCD5是鞭毛生物发生和纤毛发生所必需的，并以近原子分辨率呈现了PDCD5- tric结构的开放状态。在机械上，我们发现PDCD5通过与PhLP2A竞争与TRiC相互作用来促进底物释放，PDCD5的耗尽会在TRiC中捕获鞭毛和纤毛相关蛋白，最终导致小鼠纤毛细胞中精子鞭毛和纤毛畸形。此外，我们证明了PDCD5在鞭毛和纤毛发生中的功能取决于其C端与TRiC的相互作用。这些发现确定了PDCD5作为一种tri调节因子来促进一组蛋白质的释放。

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引用次数: 0

The ribosome synchronizes folding and assembly to promote oligomeric protein biogenesis 核糖体同步折叠和组装以促进低聚蛋白的生物发生

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2026-01-19 DOI: 10.1016/j.molcel.2025.12.022

Alžběta Roeselová, Santosh Shivakumaraswamy, Gabija Jurkeviciute, Jessica Zhiyun He, Josef Auburger, Jaro L. Schmitt, Günter Kramer, Bernd Bukau, Radoslav I. Enchev, David Balchin

引用次数: 0

Molecular mechanism of MDA5 nucleation and filament formation by LGP2 LGP2诱导MDA5成核和成丝的分子机制

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2026-01-19 DOI: 10.1016/j.molcel.2025.12.019

Nina Kurihara, Yukari Isayama, Jiayan Zhang, Takashi Yamashita, Kentaro Awaji, Yukiko Ito, Ayumi Yoshizaki, Takahisa Kouwaki, Hiroyuki Oshiumi, Hiroshi Nishimasu, Mikihiro Shibata, Osamu Nureki, Kazuki Kato

LGP2, a RIG-I-like receptor, plays a crucial role in antiviral immunity by enhancing MDA5 activity against specific viral infections. Here, using biochemical assays, cryo-electron microscopy (cryo-EM), and high-speed atomic force microscopy, we reveal that LGP2 initially binds to the ends of double-stranded RNA (dsRNA) and subsequently translocates along the RNA via ATP hydrolysis. Our cryo-EM structure demonstrates that LGP2 forms filament-like assemblies with MDA5 along the internal region of dsRNA, promoting MDA5 filament nucleation. Additionally, LGP2 and MDA5 form short RNA filaments, which are further cross-bridged via caspase activation and recruitment domain (CARD)-CARD interactions, leading to the formation of filament microclusters. These microclusters, in turn, stimulate mitochondrial antiviral signaling (MAVS) filament formation. Our findings uncover a dynamic interplay between LGP2 and MDA5, revealing a previously unrecognized mechanism that enhances antiviral immune responses.

LGP2是一种rig - i样受体，通过增强MDA5对特定病毒感染的活性，在抗病毒免疫中发挥关键作用。通过生化分析、低温电子显微镜（cro - em）和高速原子力显微镜，我们发现LGP2最初结合到双链RNA （dsRNA）的末端，随后通过ATP水解沿着RNA易位。我们的低温电镜结构表明，LGP2与MDA5沿着dsRNA的内部区域形成丝状组装，促进MDA5丝成核。此外，LGP2和MDA5形成短RNA细丝，这些短RNA细丝通过caspase激活和招募域(CARD)-CARD相互作用进一步交叉桥接，导致细丝微团簇的形成。这些微团簇反过来刺激线粒体抗病毒信号（MAVS）丝的形成。我们的研究结果揭示了LGP2和MDA5之间的动态相互作用，揭示了一种以前未被认识到的增强抗病毒免疫反应的机制。

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引用次数: 0

Dominant-negative TP53 mutations potentiated by the HSF1-regulated proteostasis network 显性阴性TP53突变被hsf1调控的蛋白平衡网络增强

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2026-01-14 DOI: 10.1016/j.molcel.2025.12.013

Stephanie Halim, Rebecca M. Sebastian, Kristi E. Liivak, Jessica E. Patrick, Tiffani Hui, David R. Amici, Andrew O. Giacomelli, Paulina Rios, Vincent L. Butty, William C. Hahn, Francisco J. Sánchez-Rivera, Marc L. Mendillo, Yu-Shan Lin, Matthew D. Shoulders

Protein mutational landscapes are shaped by how amino acid substitutions affect stability and folding or aggregation kinetics. These properties are modulated by cellular proteostasis networks. Heat shock factor 1 (HSF1) is the master regulator of cytosolic and nuclear proteostasis. Chronic HSF1 activity upregulation is a hallmark of cancer cells, potentially because upregulated proteostasis factors facilitate the acquisition and maintenance of oncogenic mutations. Here, we assess how HSF1 activation influences mutational trajectories by which p53 can escape cytotoxic pressure from nutlin-3, an inhibitor of the p53 regulator mouse double minute 2 homolog (MDM2). HSF1 activation broadly increases the fitness of dominant-negative p53 substitutions, particularly non-conservative, biophysically unfavorable amino acid changes within buried regions of the p53 DNA-binding domain. These findings demonstrate that HSF1 activation reshapes the oncogenic mutational landscape by preferentially supporting the emergence and persistence of biophysically disruptive, cancer-associated p53 substitutions, linking proteostasis network activity directly to oncogenic evolution.

蛋白质突变景观是由氨基酸取代如何影响稳定性和折叠或聚集动力学形成的。这些特性是由细胞蛋白酶抑制网络调节的。热休克因子1 （HSF1）是胞浆和核蛋白稳态的主要调节因子。慢性HSF1活性上调是癌细胞的一个标志，可能是因为上调的蛋白酶抑制因子促进了致癌突变的获得和维持。在这里，我们评估了HSF1的激活如何影响p53的突变轨迹，从而使p53逃避来自nutlin-3的细胞毒性压力，nutlin-3是p53调节因子小鼠双分钟2同源物（MDM2）的抑制剂。HSF1的激活广泛地增加了显性阴性p53替换的适应度，特别是p53 dna结合域隐藏区域内非保守的、对生物物理不利的氨基酸变化。这些发现表明，HSF1激活通过优先支持生物物理破坏性的、与癌症相关的p53替代的出现和持续，从而重塑了致癌突变景观，将蛋白质平衡网络活性直接与致癌进化联系起来。

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引用次数: 0

Delineating the copy-number substructure of metastatic tumors with CopyKit 用CopyKit描述转移性肿瘤的拷贝数亚结构

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2026-01-13 DOI: 10.1016/j.molcel.2025.12.026

Junke Wang, Darlan Conterno Minussi, Alexander Davis, Runmin Wei, Hanghui Ye, Emi Sei, Aislyn Schalck, Yun Yan, Hua-Jun Wu, Shanshan Bai, Cheng Peng, Min Hu, Anna Casasent, Alejandro Contreras, Hui Chen, David Hui, Senthil Damodaran, Mary E. Edgerton, Scott Kopetz, Bora Lim, Nicholas Navin

Tumors are composed of a myriad of subclones that bulk DNA sequencing (DNA-seq) methods cannot accurately resolve. Single-cell DNA-seq methods were developed to address this issue, yet their data analysis remains challenging. Here, we present CopyKit, a comprehensive tool for single-cell DNA copy-number analysis to resolve clonal substructure and reconstruct genetic lineages. Additionally, we introduce “scquantum” to estimate the integer copy-number states of single cells. We performed single-cell DNA-seq of 11,845 cells from one primary breast tumor, two liver metastases, and three primary tumors with matched metastatic tissues. These data identified the subclones from the primary tumors that seeded the metastatic lesions and their associated copy-number events. The data also provided evidence of both subclonal intermixing and spatial segregation in different regions of the liver metastasis. These applications show that CopyKit is a powerful approach for the analysis of high-throughput single-cell copy-number data.

肿瘤是由大量DNA测序（DNA-seq）方法无法准确分辨的无数亚克隆组成的。单细胞dna测序方法被开发来解决这个问题，但他们的数据分析仍然具有挑战性。在这里，我们提出了CopyKit，一个单细胞DNA拷贝数分析的综合工具，以解决克隆亚结构和重建遗传谱系。此外，我们引入了“scquantum”来估计单个细胞的整数拷贝数状态。我们对11,845个细胞进行了单细胞dna测序，这些细胞来自1例原发性乳腺肿瘤、2例肝脏转移瘤和3例具有匹配转移组织的原发性肿瘤。这些数据确定了来自播下转移性病变种子的原发肿瘤的亚克隆及其相关的拷贝数事件。这些数据还提供了亚克隆混合和空间分离在不同区域的肝转移的证据。这些应用表明，CopyKit是一种分析高通量单细胞拷贝数数据的强大方法。

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引用次数: 0

Finding an Achilles' heel of cancer cells: Exonized Alu elements in AURKA. 发现癌细胞的阿喀琉斯之踵：AURKA中的外显Alu元素。

IF 16.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2026-01-08 DOI: 10.1016/j.molcel.2025.12.011

Beatrice Zhang, Omar Abdel-Wahab

In this issue of Molecular Cell, Kral et al.¹ identify a targetable, novel mechanism of pancreatic ductal adenocarcinoma (PDAC) tumorigenesis via SRSF1 splicing-mediated regulation of an Alu-derived exon in Aurora kinase A (AURKA).

在本期《分子细胞》杂志上，Kral等人通过SRSF1剪接介导的极光激酶a （AURKA）中alu衍生外显子的调控，发现了胰腺导管腺癌（PDAC）发生的一种可靶向的新机制。

引用次数: 0

Mechanical forces regulate the composition and fate of stalled nascent chains. 机械力调节着停滞的新生链条的组成和命运。

IF 16.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell

Pub Date : 2026-01-08 Epub Date: 2025-12-30 DOI: 10.1016/j.molcel.2025.12.008

Danish Khan, Ananya A Vinayak, Cole S Sitron, Onn Brandman

The ribosome-associated quality control (RQC) pathway resolves stalled ribosomes. As part of RQC, stalled nascent polypeptide chains (NCs) are appended with CArboxy-Terminal amino acid tails (CAT tails) in an mRNA-free, non-canonical elongation process. The relationship between CAT tail composition (alanine [Ala] and threonine [Thr] in yeast) and function has remained unknown. Using biochemical approaches in yeast, we discovered that mechanical forces on the NC regulate CAT tailing. We propose that CAT tailing initially operates in "extrusion mode," which increases NC lysine accessibility for on-ribosome ubiquitylation. Thr in CAT tails prevents the formation of polyalanine, which forms α-helices that lower extrusion efficiency and disrupt termination of CAT tailing. After NC ubiquitylation, pulling forces on the NC switch CAT tailing to an Ala-only "release mode," which facilitates NC release and degradation. Failure to switch from extrusion to release mode leads to the accumulation of NCs on large ribosomal subunits and proteotoxic aggregation of Thr-rich CAT tails.

核糖体相关质量控制（RQC）途径解决停滞的核糖体。作为RQC的一部分，停滞的新生多肽链（nc）在无mrna的非规范延伸过程中附加羧基末端氨基酸尾部（CAT尾部）。CAT尾部成分（酵母中丙氨酸[Ala]和苏氨酸[Thr]）与功能之间的关系尚不清楚。利用酵母的生化方法，我们发现NC上的机械力调节着CAT的尾迹。我们建议CAT尾化最初以“挤压模式”运作，这增加了核糖体上泛素化的NC赖氨酸可及性。CAT尾中的苏阻止聚丙氨酸的形成，聚丙氨酸形成α-螺旋，降低挤压效率，破坏CAT尾的终止。在NC泛素化之后，在NC开关CAT上的拉力进入仅ala的“释放模式”，从而促进NC的释放和降解。如果不能从挤压模式切换到释放模式，就会导致NCs在大型核糖体亚基上的积累和富thr3 CAT尾部的蛋白质毒性聚集。

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引用次数: 0

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