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Ubiquitylation: Sword and shield in the bacterial arsenal 泛素化:细菌武库中的剑与盾
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.034
Jonathan N. Pruneda, Felix Randow

In two recent studies in Nature, Hör et al.1 and Chambers et al.2 report that ubiquitin-like conjugation in bacteria antagonizes phage replication.

最近在《自然》杂志上发表的两项研究中,Hör 等人1 和 Chambers 等人2 报告说,细菌中的泛素类连接能拮抗噬菌体的复制。
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引用次数: 0
Finish the unfinished: Chd1 resolving hexasome-nucleosome complex with FACT 完成未完成的工作Chd1 与 FACT 一起解析六聚体-核小体复合物
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.031
Hongxin Yin, Yang Liu

In this issue of Molecular Cell, Engeholm et al.1 present cryo-EM structures of the chromatin remodeler Chd1 bound to a hexasome-nucleosome complex, an intermediate state during transcription either with or without FACT to restore the missing H2A-H2B dimer. These two binding modes reveal how Chd1 and FACT cooperate in nucleosome re-establishment during transcription.

在本期的《分子细胞》(Molecular Cell)杂志上,Engeholm 等人1 展示了染色质重塑者 Chd1 与六聚体-核小体复合物结合的冷冻电镜结构,六聚体-核小体复合物是转录过程中的中间状态,可与 FACT 结合或不与 FACT 结合,以恢复缺失的 H2A-H2B 二聚体。这两种结合模式揭示了 Chd1 和 FACT 如何在转录过程中合作重建核小体。
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引用次数: 0
A TBK1-independent primordial function of STING in lysosomal biogenesis STING 在溶酶体生物发生过程中的原始功能与 TBK1 无关
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.026
Bo Lv, William A. Dion, Haoxiang Yang, Jinrui Xun, Do-Hyung Kim, Bokai Zhu, Jay Xiaojun Tan

Stimulator of interferon genes (STING) is activated in many pathophysiological conditions, leading to TBK1-dependent interferon production in higher organisms. However, primordial functions of STING independent of TBK1 are poorly understood. Here, through proteomics and bioinformatics approaches, we identify lysosomal biogenesis as an unexpected function of STING. Transcription factor EB (TFEB), an evolutionarily conserved regulator of lysosomal biogenesis and host defense, is activated by STING from multiple species, including humans, mice, and frogs. STING-mediated TFEB activation is independent of TBK1, but it requires STING trafficking and its conserved proton channel. GABARAP lipidation, stimulated by the channel of STING, is key for STING-dependent TFEB activation. STING stimulates global upregulation of TFEB-target genes, mediating lysosomal biogenesis and autophagy. TFEB supports cell survival during chronic sterile STING activation, a common condition in aging and age-related diseases. These results reveal a primordial function of STING in the biogenesis of lysosomes, essential organelles in immunity and cellular stress resistance.

干扰素基因刺激器(STING)在许多病理生理条件下被激活,导致高等生物产生依赖于 TBK1 的干扰素。然而,人们对 STING 独立于 TBK1 的原始功能知之甚少。在这里,通过蛋白质组学和生物信息学方法,我们发现溶酶体生物生成是 STING 的一项意想不到的功能。转录因子 EB(TFEB)是溶酶体生物生成和宿主防御的进化保守调节因子,它被包括人类、小鼠和青蛙在内的多个物种的 STING 激活。STING 介导的 TFEB 激活与 TBK1 无关,但需要 STING 的贩运及其保守的质子通道。由 STING 通道刺激的 GABARAP 脂化是 STING 依赖性 TFEB 激活的关键。STING 可刺激 TFEB 靶基因的全面上调,介导溶酶体的生物生成和自噬。在慢性无菌 STING 激活过程中,TFEB 支持细胞存活,这是衰老和与年龄相关疾病的常见情况。这些结果揭示了 STING 在溶酶体生物发生过程中的基本功能,而溶酶体是免疫和细胞抗应激的重要细胞器。
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引用次数: 0
Coming in out of the cold: Rho-dependent termination contributes to adaptation to cold shock 从寒冷中走来依赖 Rho 的终止有助于适应冷休克
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.033
Teppei Morita, Susan Gottesman

During cold shock, bacteria shut down translation of all but a set of cold-shock proteins critical for recovery; in this issue of Molecular Cell, Delaleau et al.1 show that Rho-dependent transcription termination plays an important role in cold adaptation, via temperature-regulated termination of the cold-shock protein mRNAs.

在本期《分子细胞》杂志上,Delaleau 等人1 通过温度调节冷休克蛋白 mRNA 的终止,证明 Rho 依赖性转录终止在冷适应中发挥着重要作用。
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引用次数: 0
Spatial omics advances for in situ RNA biology 空间全息技术在原位 RNA 生物学方面的进展
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-12 DOI: 10.1016/j.molcel.2024.08.002
Jingyi Ren, Shuchen Luo, Hailing Shi, Xiao Wang

Spatial regulation of RNA plays a critical role in gene expression regulation and cellular function. Understanding spatially resolved RNA dynamics and translation is vital for bringing new insights into biological processes such as embryonic development, neurobiology, and disease pathology. This review explores past studies in subcellular, cellular, and tissue-level spatial RNA biology driven by diverse methodologies, ranging from cell fractionation, in situ and proximity labeling, imaging, spatially indexed next-generation sequencing (NGS) approaches, and spatially informed computational modeling. Particularly, recent advances have been made for near-genome-scale profiling of RNA and multimodal biomolecules at high spatial resolution. These methods enabled new discoveries into RNA’s spatiotemporal kinetics, RNA processing, translation status, and RNA-protein interactions in cells and tissues. The evolving landscape of experimental and computational strategies reveals the complexity and heterogeneity of spatial RNA biology with subcellular resolution, heralding new avenues for RNA biology research.

RNA 的空间调控在基因表达调控和细胞功能中起着至关重要的作用。了解空间解析的 RNA 动态和翻译对于深入了解胚胎发育、神经生物学和疾病病理学等生物过程至关重要。本综述探讨了过去在亚细胞、细胞和组织级空间 RNA 生物学方面的研究,这些研究采用了多种方法,包括细胞分馏、原位和近距离标记、成像、空间索引下一代测序(NGS)方法和空间知情计算建模。特别是最近在高空间分辨率下对 RNA 和多模态生物大分子进行近基因组尺度剖析方面取得了进展。这些方法使人们对 RNA 的时空动力学、RNA 加工、翻译状态以及细胞和组织中 RNA 蛋白相互作用有了新的发现。不断发展的实验和计算策略揭示了亚细胞分辨率空间 RNA 生物学的复杂性和异质性,预示着 RNA 生物学研究的新途径。
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引用次数: 0
Resolution of transcription-induced hexasome-nucleosome complexes by Chd1 and FACT 通过 Chd1 和 FACT 分解转录诱导的六聚体-核小体复合物
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-12 DOI: 10.1016/j.molcel.2024.08.022
Maik Engeholm, Johann J. Roske, Elisa Oberbeckmann, Christian Dienemann, Michael Lidschreiber, Patrick Cramer, Lucas Farnung

To maintain the nucleosome organization of transcribed genes, ATP-dependent chromatin remodelers collaborate with histone chaperones. Here, we show that at the 5′ ends of yeast genes, RNA polymerase II (RNAPII) generates hexasomes that occur directly adjacent to nucleosomes. The resulting hexasome-nucleosome complexes are then resolved by Chd1. We present two cryoelectron microscopy (cryo-EM) structures of Chd1 bound to a hexasome-nucleosome complex before and after restoration of the missing inner H2A/H2B dimer by FACT. Chd1 uniquely interacts with the complex, positioning its ATPase domain to shift the hexasome away from the nucleosome. In the absence of the inner H2A/H2B dimer, its DNA-binding domain (DBD) packs against the ATPase domain, suggesting an inhibited state. Restoration of the dimer by FACT triggers a rearrangement that displaces the DBD and stimulates Chd1 remodeling. Our results demonstrate how chromatin remodelers interact with a complex nucleosome assembly and suggest how Chd1 and FACT jointly support transcription by RNAPII.

为了维持转录基因的核小体组织,依赖 ATP 的染色质重塑者与组蛋白伴侣合作。在这里,我们发现在酵母基因的 5′末端,RNA 聚合酶 II(RNAPII)会产生直接毗邻核小体的六聚体。产生的六聚体-核小体复合物随后被 Chd1 分解。我们展示了 Chd1 与六聚体-核小体复合物结合的两种冷冻电子显微镜(cryo-EM)结构,分别发生在通过 FACT 恢复缺失的内部 H2A/H2B 二聚体之前和之后。Chd1 与复合物独特地相互作用,定位其 ATPase 结构域,使六聚体远离核糖体。在缺乏内部 H2A/H2B 二聚体的情况下,其 DNA 结合结构域 (DBD) 会与 ATPase 结构域相抵触,这表明它处于抑制状态。通过 FACT 恢复二聚体会引发重排,从而移位 DBD 并刺激 Chd1 重塑。我们的研究结果证明了染色质重塑者如何与复杂的核小体组装相互作用,并表明 Chd1 和 FACT 如何共同支持 RNAPII 的转录。
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引用次数: 0
RAPIDASH: Tag-free enrichment of ribosome-associated proteins reveals composition dynamics in embryonic tissue, cancer cells, and macrophages RAPIDASH:无标记核糖体相关蛋白富集揭示胚胎组织、癌细胞和巨噬细胞中的组成动态
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-10 DOI: 10.1016/j.molcel.2024.08.023
Teodorus Theo Susanto, Victoria Hung, Andrew G. Levine, Yuxiang Chen, Craig H. Kerr, Yongjin Yoo, Juan A. Oses-Prieto, Lisa Fromm, Zijian Zhang, Travis C. Lantz, Kotaro Fujii, Marius Wernig, Alma L. Burlingame, Davide Ruggero, Maria Barna

Ribosomes are emerging as direct regulators of gene expression, with ribosome-associated proteins (RAPs) allowing ribosomes to modulate translation. Nevertheless, a lack of technologies to enrich RAPs across sample types has prevented systematic analysis of RAP identities, dynamics, and functions. We have developed a label-free methodology called RAPIDASH to enrich ribosomes and RAPs from any sample. We applied RAPIDASH to mouse embryonic tissues and identified hundreds of potential RAPs, including Dhx30 and Llph, two forebrain RAPs important for neurodevelopment. We identified a critical role of LLPH in neural development linked to the translation of genes with long coding sequences. In addition, we showed that RAPIDASH can identify ribosome changes in cancer cells. Finally, we characterized ribosome composition remodeling during immune cell activation and observed extensive changes post-stimulation. RAPIDASH has therefore enabled the discovery of RAPs in multiple cell types, tissues, and stimuli and is adaptable to characterize ribosome remodeling in several contexts.

核糖体正在成为基因表达的直接调节器,核糖体相关蛋白(RAPs)使核糖体能够调节翻译。然而,由于缺乏在不同样本类型中富集 RAPs 的技术,因此无法对 RAP 的特性、动态和功能进行系统分析。我们开发了一种名为 RAPIDASH 的无标记方法,可从任何样本中富集核糖体和 RAPs。我们将 RAPIDASH 应用于小鼠胚胎组织,发现了数百个潜在的 RAPs,包括 Dhx30 和 Llph 这两个对神经发育很重要的前脑 RAPs。我们确定了 LLPH 在神经发育中的关键作用,它与长编码序列基因的翻译有关。此外,我们还发现 RAPIDASH 可以识别癌细胞中核糖体的变化。最后,我们描述了免疫细胞活化过程中核糖体组成重塑的特点,并观察到刺激后的广泛变化。因此,RAPIDASH 能够发现多种细胞类型、组织和刺激下的 RAPs,并能适应多种情况下核糖体重塑的特征。
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引用次数: 0
Targeting APT2 improves MAVS palmitoylation and antiviral innate immunity 靶向 APT2 可改善 MAVS 棕榈酰化和抗病毒先天免疫力
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-09 DOI: 10.1016/j.molcel.2024.08.014
Lang Bu, Huan Wang, Shuishen Zhang, Yi Zhang, Miaowen Liu, Zhengkun Zhang, Xueji Wu, Qiwei Jiang, Lei Wang, Wei Xie, Miao He, Zhengran Zhou, Chao Cheng, Jianping Guo

Innate immunity serves as the primary defense against viral and microbial infections in humans. The precise influence of cellular metabolites, especially fatty acids, on antiviral innate immunity remains largely elusive. Here, through screening a metabolite library, palmitic acid (PA) has been identified as a key modulator of antiviral infections in human cells. Mechanistically, PA induces mitochondrial antiviral signaling protein (MAVS) palmitoylation, aggregation, and subsequent activation, thereby enhancing the innate immune response. The palmitoyl-transferase ZDHHC24 catalyzes MAVS palmitoylation, thereby boosting the TBK1-IRF3-interferon (IFN) pathway, particularly under conditions of PA stimulation or high-fat-diet-fed mouse models, leading to antiviral immune responses. Additionally, APT2 de-palmitoylates MAVS, thus inhibiting antiviral signaling, suggesting that its inhibitors, such as ML349, effectively reverse MAVS activation in response to antiviral infections. These findings underscore the critical role of PA in regulating antiviral innate immunity through MAVS palmitoylation and provide strategies for enhancing PA intake or targeting APT2 for combating viral infections.

先天免疫是人类抵御病毒和微生物感染的主要防御手段。细胞代谢物(尤其是脂肪酸)对抗病毒先天免疫的确切影响在很大程度上仍然难以捉摸。在这里,通过筛选代谢物库,发现棕榈酸(PA)是人类细胞抗病毒感染的关键调节剂。从机理上讲,棕榈酸能诱导线粒体抗病毒信号蛋白(MAVS)棕榈酰化、聚集和随后的活化,从而增强先天性免疫反应。棕榈酰转移酶 ZDHHC24 可催化 MAVS 的棕榈酰化,从而促进 TBK1-IRF3- 干扰素(IFN)通路,尤其是在 PA 刺激或高脂饮食小鼠模型条件下,从而导致抗病毒免疫反应。此外,APT2 可使 MAVS 去棕榈酰化,从而抑制抗病毒信号传导,这表明其抑制剂(如 ML349)可有效逆转 MAVS 在抗病毒感染中的激活。这些发现强调了 PA 在通过 MAVS 棕榈酰化调节抗病毒先天性免疫中的关键作用,并为提高 PA 摄入量或靶向 APT2 抗病毒感染提供了策略。
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引用次数: 0
Heterochromatin: Hiding from the remodeling machines 异染色质:躲避重塑机器的攻击
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.molcel.2024.08.012
Craig L. Peterson

In this issue of Molecular Cell, Sahu et al.1 find that shielding heterochromatin from SWI/SNF chromatin remodelers is essential to maintain and epigenetically propagate pre-existing heterochromatin domains, whereas SWI/SNF action protects facultative heterochromatic regions from premature silencing.

在本期的《分子细胞》(Molecular Cell)杂志上,Sahu 等人1 发现,保护异染色质不受 SWI/SNF 染色质重塑者的影响,对于维持和表观遗传学上传播先前存在的异染色质结构域至关重要,而 SWI/SNF 的作用则能保护变性异染色质区域免于过早沉默。
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引用次数: 0
Anti-CRISPRs deconstruct bacterial defense 抗CRISPR解构细菌防御系统
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.molcel.2024.08.008
Nils Birkholz, Peter C. Fineran

Deploying anti-CRISPR proteins is a potent strategy used by phages to inhibit bacterial CRISPR-Cas defense. In a new Nature paper, Trost et al.1 discover and characterize an exciting anti-CRISPR mechanism with possible implications beyond this microscopic arms race.

部署抗 CRISPR 蛋白是噬菌体用来抑制细菌 CRISPR-Cas 防御的一种有效策略。在新发表的《自然》(Nature)论文中,特罗斯特等人1 发现并描述了一种令人兴奋的反CRISPR机制,其影响可能超出这场微观军备竞赛。
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引用次数: 0
期刊
Molecular Cell
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