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OXCT1 succinylation and activation by SUCLA2 promotes ketolysis and liver tumor growth
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-24 DOI: 10.1016/j.molcel.2024.12.025
Dong Guo, Qiujing Yu, Yingying Tong, Xu Qian, Ying Meng, Fei Ye, Xiaoming Jiang, Lihui Wu, Qingqing Yang, Suyao Li, Min Li, Qingang Wu, Liwei Xiao, Xuxiao He, Rongxuan Zhu, Guijun Liu, Dou Nie, Shudi Luo, Leina Ma, Ren-an Jin, Zhimin Lu
Ketone bodies generated in hepatocytes in the adult liver are used for nonhepatic tissues as an energy source. However, ketolysis is reactivated in hepatocellular carcinoma (HCC) cells with largely unelucidated mechanisms. Here, we demonstrate that 3-oxoacid CoA-transferase 1 (OXCT1), a rate-limiting enzyme in ketolysis, interacts with SUCLA2 upon IGF1 stimulation in HCC cells. This interaction results from ERK2-mediated SUCLA2 S124 phosphorylation and subsequent PIN1-mediated cis-trans isomerization of SUCLA2. OXCT1-associated SUCLA2 generates succinyl-CoA, which not only serves as a substrate for OXCT1 but also directly succinylates OXCT1 at K421 and activates OXCT1. SUCLA2-regulated OXCT1 activation substantially enhances ketolysis, HCC cell proliferation, and tumor growth in mice. Notably, treatment with acetohydroxamic acid, an OXCT1 inhibitor used clinically for urinary infection, inhibits liver tumor growth in mice and significantly enhances lenvatinib therapy. Our findings highlight the role of SUCLA2-coupled regulation of OXCT1 succinylation in ketolysis and unveil an unprecedented strategy for treating HCC by interrupting ketolysis.
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引用次数: 0
Cytoplasmic mRNA decay controlling inflammatory gene expression is determined by pre-mRNA fate decision
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-24 DOI: 10.1016/j.molcel.2025.01.001
Annika Bestehorn, Julius von Wirén, Christina Zeiler, Jeanne Fesselet, Sebastian Didusch, Maurizio Forte, Kevin Doppelmayer, Martina Borroni, Anita Le Heron, Sara Scinicariello, WeiQiang Chen, Manuela Baccarini, Vera Pfanzagl, Gijs A. Versteeg, Markus Hartl, Pavel Kovarik
The fidelity of immune responses depends on timely controlled and selective mRNA degradation that is largely driven by RNA-binding proteins (RBPs). It remains unclear whether stochastic or directed processes govern the selection of an individual mRNA molecule for degradation. Using human and mouse cells, we show that tristetraprolin (TTP, also known as ZFP36), an essential anti-inflammatory RBP, destabilizes target mRNAs via a hierarchical molecular assembly. The assembly formation strictly relies on the interaction of TTP with RNA. The TTP homolog ZFP36L1 exhibits similar requirements, indicating a broader relevance of this regulatory program. Unexpectedly, the assembly of the cytoplasmic mRNA-destabilization complex is licensed in the nucleus by TTP binding to pre-mRNA, which we identify as the principal TTP target rather than mRNA. Hence, the fate of an inflammation-induced mRNA is decided concomitantly with its synthesis. This mechanism prevents the translation of excessive and potentially harmful inflammation mediators, irrespective of transcription.
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引用次数: 0
Microexon in action: How tiny fragments in a protein tune function, drive disease 微外显子的作用:蛋白质中的微小片段如何调节功能,驱动疾病
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-16 DOI: 10.1016/j.molcel.2024.12.022
Jie-rong Huang
Intrinsically disordered regions (IDRs) of proteins can regulate function through phase separation. In a recent article in Nature, Garcia-Cabau et al. reveal that including or excluding a microexon within the IDR of CPEB4 alters its condensation properties, suggesting a potential mechanism underlying autism spectrum disorder.1
蛋白质的本征无序区(IDR)可以通过相分离调节功能。Garcia-Cabau 等人最近在《自然》(Nature)杂志上发表文章,揭示了在 CPEB4 的 IDR 中加入或排除一个微外显子会改变其凝结特性,从而提出了自闭症谱系障碍的潜在机制1。
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引用次数: 0
Molecular determinants of condensate composition 冷凝物组成的分子决定因素
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-16 DOI: 10.1016/j.molcel.2024.12.021
Alex S. Holehouse, Simon Alberti
Cells use membraneless compartments to organize their interiors, and recent research has begun to uncover the molecular principles underlying their assembly. Here, we explore how site-specific and chemically specific interactions shape the properties and functions of condensates. Site-specific recruitment involves precise interactions at specific sites driven by partially or fully structured interfaces. In contrast, chemically specific recruitment is driven by complementary chemical interactions without the requirement for a persistent bound-state structure. We propose that site-specific and chemically specific interactions work together to determine the composition of condensates, facilitate biochemical reactions, and regulate enzymatic activities linked to metabolism, signaling, and gene expression. Characterizing the composition of condensates requires novel experimental and computational tools to identify and manipulate the molecular determinants guiding condensate recruitment. Advancing this research will deepen our understanding of how condensates regulate cellular functions, providing valuable insights into cellular physiology and organization.
细胞利用无膜隔室来组织内部结构,最近的研究已开始揭示其组装的分子原理。在这里,我们探讨了特定位点和化学特异性相互作用如何塑造凝聚体的特性和功能。位点特异性招募涉及由部分或完全结构化界面驱动的特定位点上的精确相互作用。相比之下,化学特异性招募是由互补的化学相互作用驱动的,不需要持久的结合态结构。我们认为,位点特异性和化学特异性相互作用共同决定了凝聚物的组成,促进了生化反应,并调节了与新陈代谢、信号传导和基因表达相关的酶活性。表征凝集物的组成需要新的实验和计算工具,以确定和操纵引导凝集物招募的分子决定因素。推进这项研究将加深我们对凝集素如何调控细胞功能的理解,为细胞生理学和组织学提供有价值的见解。
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引用次数: 0
Nucleic acid recognition during prokaryotic immunity 原核免疫过程中的核酸识别
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-16 DOI: 10.1016/j.molcel.2024.12.007
Christian F. Baca, Luciano A. Marraffini
Parasitic elements often spread to hosts through the delivery of their nucleic acids to the recipient. This is particularly true for the primary parasites of bacteria, bacteriophages (phages) and plasmids. Although bacterial immune systems can sense a diverse set of infection signals, such as a protein unique to the invader or the disruption of natural host processes, phage and plasmid nucleic acids represent some of the most common molecules that are recognized as foreign to initiate defense. In this review, we will discuss the various elements of invader nucleic acids that can be distinguished by bacterial host immune systems as “non-self” and how this signal is relayed to activate an immune response.
寄生元素通常通过向受体传递核酸来传播宿主。细菌的主要寄生虫--噬菌体和质粒尤其如此。虽然细菌免疫系统能感知多种感染信号,如入侵者特有的蛋白质或宿主自然过程的破坏,但噬菌体和质粒核酸是一些最常见的分子,它们被识别为外来分子,从而启动防御。在这篇综述中,我们将讨论细菌宿主免疫系统可将入侵者核酸中的各种元素区分为 "非自身",以及如何传递这一信号以激活免疫反应。
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引用次数: 0
Ubiquitin—A structural perspective 泛素a结构的观点
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-16 DOI: 10.1016/j.molcel.2024.12.015
Rashmi Agrata, David Komander
The modification of proteins and other biomolecules with the small protein ubiquitin has enthralled scientists from many disciplines for decades, creating a broad research field. Ubiquitin research is particularly rich in molecular and mechanistic understanding due to a plethora of (poly)ubiquitin structures alone and in complex with ubiquitin machineries. Furthermore, due to its favorable properties, ubiquitin serves as a model system for many biophysical and computational techniques. Here, we review the current knowledge of ubiquitin signals through a ubiquitin-centric, structural biology lens. We amalgamate the information from 240 structures in the Protein Data Bank (PDB), combined with single-molecule, molecular dynamics, and nuclear magnetic resonance (NMR) studies, to provide a comprehensive picture of ubiquitin and polyubiquitin structures and dynamics. We close with a discussion of the latest frontiers in ubiquitin research, namely the modification of ubiquitin by other post-translational modifications (PTMs) and the notion that ubiquitin is attached to biomolecules beyond proteins.
几十年来,用小蛋白泛素修饰蛋白质和其他生物大分子的研究令许多学科的科学家着迷,形成了一个广阔的研究领域。由于存在大量单独的(多)泛素结构以及与泛素机制的复合结构,泛素研究在分子和机理方面的内容尤为丰富。此外,由于泛素具有良好的特性,它还是许多生物物理和计算技术的模型系统。在这里,我们通过以泛素为中心的结构生物学视角,回顾了目前有关泛素信号的知识。我们综合了蛋白质数据库(PDB)中 240 种结构的信息,并结合单分子、分子动力学和核磁共振(NMR)研究,提供了泛素和多泛素结构与动力学的全面图景。最后,我们将讨论泛素研究的最新前沿,即其他翻译后修饰(PTM)对泛素的修饰,以及泛素附着于蛋白质以外的生物大分子的概念。
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引用次数: 0
Dynamic histone modification patterns coordinating DNA processes 动态组蛋白修饰模式协调DNA过程
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-16 DOI: 10.1016/j.molcel.2024.10.034
Laura López-Hernández, Patrick Toolan-Kerr, Andrew J. Bannister, Gonzalo Millán-Zambrano
Significant effort has been spent attempting to unravel the causal relationship between histone post-translational modifications and fundamental DNA processes, including transcription, replication, and repair. However, less attention has been paid to understanding the reciprocal influence—that is, how DNA processes, in turn, shape the distribution and patterns of histone modifications and how these changes convey information, both temporally and spatially, from one process to another. Here, we review how histone modifications underpin the widespread bidirectional crosstalk between different DNA processes, which allow seemingly distinct phenomena to operate as a unified whole.
人们花费了大量精力试图揭示组蛋白翻译后修饰与 DNA 基本过程(包括转录、复制和修复)之间的因果关系。然而,人们较少关注对相互影响的理解,即 DNA 过程如何反过来影响组蛋白修饰的分布和模式,以及这些变化如何在时间和空间上将信息从一个过程传递到另一个过程。在这里,我们将回顾组蛋白修饰是如何支撑不同DNA过程之间广泛的双向串扰,从而使看似不同的现象作为一个统一的整体运作。
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引用次数: 0
Bridging the gap: How enhancers cooperate to regulate gene expression over large genomic distances 弥合差距:增强子如何在大基因组距离上合作调节基因表达
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-16 DOI: 10.1016/j.molcel.2024.12.001
Dimitra Tsouraki, A. Marieke Oudelaar
By building synthetic regulatory landscapes, Jensen et al.1 and Thomas et al.2 demonstrate in this issue of Molecular Cell that gene expression levels strongly depend on the genomic distance between enhancers and promoters and that enhancer cooperation can compensate for reduced enhancer activity over large genomic distances.
通过构建合成调控景观,Jensen等人1和Thomas等人2在本期《分子细胞》中证明,基因表达水平强烈依赖于增强子和启动子之间的基因组距离,并且增强子的合作可以弥补大基因组距离上增强子活性的降低。
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引用次数: 0
Charting the epitranscriptomic landscape across RNA biotypes using native RNA nanopore sequencing 利用天然RNA纳米孔测序绘制RNA生物型的表转录组学景观
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-16 DOI: 10.1016/j.molcel.2024.12.014
Gregor Diensthuber, Eva Maria Novoa
RNA modifications are conserved chemical features found in all domains of life and across diverse RNA biotypes, shaping gene expression profiles and enabling rapid responses to environmental changes. Their broad chemical diversity and dynamic nature pose significant challenges for studying them comprehensively. These limitations can now be addressed through direct RNA nanopore sequencing (DRS), which allows simultaneous identification of diverse RNA modification types at single-molecule and single-nucleotide resolution. Here, we review recent efforts pioneering the use of DRS to better understand the epitranscriptomic landscape. We highlight how DRS can be applied to investigate different RNA biotypes, emphasizing the use of specialized library preparation protocols and downstream bioinformatic workflows to detect both natural and synthetic RNA modifications. Finally, we provide a perspective on the future role of DRS in epitranscriptomic research, highlighting remaining challenges and emerging opportunities from improved sequencing yields and accuracy enabled by the latest DRS chemistry.
RNA 修饰是所有生命领域和各种 RNA 生物类型中都有的保守的化学特征,可塑造基因表达谱并对环境变化做出快速反应。其广泛的化学多样性和动态性质为全面研究它们带来了巨大挑战。现在可以通过直接 RNA 纳米孔测序(DRS)来解决这些限制,DRS 允许以单分子和单核苷酸分辨率同时鉴定各种 RNA 修饰类型。在此,我们回顾了最近率先使用 DRS 来更好地了解表转录组的工作。我们重点介绍了 DRS 如何应用于研究不同的 RNA 生物类型,强调使用专门的文库制备协议和下游生物信息学工作流程来检测天然和合成 RNA 修饰。最后,我们展望了 DRS 在表转录组学研究中的未来作用,强调了最新 DRS 化学技术提高测序产量和准确性所带来的挑战和机遇。
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引用次数: 0
Artificial intelligence in molecular biology 分子生物学中的人工智能
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-16 DOI: 10.1016/j.molcel.2024.12.013
Anshul Kundaje, Katherine S. Pollard, Jian Ma, Xing Chang, Mengjie Chen, Remo Rohs
In recent years, computational methods and artificial intelligence approaches have proven uniquely suited for studying patterns in molecular biology. In this focus issue, we spoke with researchers about using these tools to address various biological questions and explore both current implications and future possibilities.
近年来,计算方法和人工智能方法被证明非常适合研究分子生物学中的模式。在本期焦点问题中,我们与研究人员讨论了如何使用这些工具来解决各种生物学问题,并探索当前的影响和未来的可能性。
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引用次数: 0
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Molecular Cell
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