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Transcriptomic insights into the virulence of Acinetobacter baumannii during infection-role of iron uptake and siderophore production genes. 通过转录组深入了解鲍曼不动杆菌感染期间的毒力--铁吸收基因和嗜苷酸生产基因的作用。
IF 3.5 4区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-11-21 DOI: 10.1002/1873-3468.15061
Kah Ern Ten, Sadequr Rahman, Hock Siew Tan

Acinetobacter baumannii, a top-priority WHO pathogen, causes life-threatening infections in immunocompromised patients, leading to prolonged hospitalisation and high mortality. Here, we used the Galleria mellonella model to investigate community strain C98 (Ab-C98) virulence via transcriptomic analysis. Ab-C98 showed greater killing and faster colonisation in larvae than the clinical reference strain (ATCC BAA1605). Genes in three iron clusters, acinetobactin, baumannoferrin and the Feo system, were significantly up-regulated. Targeted knockout of siderophore genes (basC, bfnD, and the gene encoding isochorismatase) significantly increased the survival of infected larvae by at least 35.16%, identifying these genes as potential targets for developing anti-virulence agents against A. baumannii.

鲍曼不动杆菌(Acinetobacter baumannii)是世界卫生组织最优先处理的病原体,它在免疫力低下的患者中引起危及生命的感染,导致长期住院和高死亡率。在这里,我们利用鹅膏蕈模型,通过转录组分析研究了群落菌株 C98(Ab-C98)的毒力。与临床参考菌株(ATCC BAA1605)相比,Ab-C98对幼虫的杀伤力更大,定殖速度更快。三个铁簇(乙酰胆碱、鲍曼铁蛋白和 Feo 系统)中的基因被显著上调。有针对性地敲除嗜苷基因(basC、bfnD 和编码异构酶的基因)可使受感染幼虫的存活率至少提高 35.16%,从而确定这些基因是开发鲍曼不动杆菌抗病毒药物的潜在靶标。
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引用次数: 0
Disruption of Iqsec1 in mice leads to embryonic lethality with reduced large apical vacuoles in the visceral endoderm. 在小鼠体内破坏 Iqsec1 会导致胚胎死亡,内脏内胚层的大顶端空泡减少。
IF 3.5 4区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-11-19 DOI: 10.1002/1873-3468.15058
Hiroyuki Sakagami, Tomoko Shiroshima, Noriko Nemoto, Tomoko Niimura, Takeyuki Sugawara, Yoshinobu Hara, Koji Saito, Tadashi Okubo, Masahiro Fukaya

Iqsec1 (IQ motif and Sec7 domain-containing protein 1), also known as BRAG2 (Brefeldin A-resistant Arf-GEF 2), is a guanine nucleotide exchange factor that regulates membrane trafficking, cytoskeletal organization, and signal transduction by activating class II and III ADP-ribosylation factors. To investigate the physiological role of Iqsec1 at the whole animal level, we generated Iqsec1-deficient mice using CRISPR/Cas9-mediated gene editing. Nearly all Iqsec1-/- mice (99%) exhibited embryonic lethality with severe growth retardation. Electron microscopy revealed that Iqsec1-/- embryos at embryonic day 8.5 lacked large apical vacuoles in visceral endoderm cells of the yolk sac, compared with controls. These findings suggest that Iqsec1 plays a critical role in embryogenesis, likely through regulation of membrane trafficking in visceral endoderm cells.

Iqsec1(IQ motif and Sec7 domain-containing protein 1)又称BRAG2(Brefeldin A-resistant Arf-GEF 2),是一种鸟嘌呤核苷酸交换因子,它通过激活II类和III类ADP-核糖基化因子来调节膜贩运、细胞骨架组织和信号转导。为了研究Iqsec1在整个动物水平上的生理作用,我们利用CRISPR/Cas9介导的基因编辑技术产生了Iqsec1缺陷小鼠。几乎所有 Iqsec1-/- 小鼠(99%)都表现出胚胎致死和严重的生长迟缓。电子显微镜显示,与对照组相比,Iqsec1-/-胚胎在胚胎第8.5天时,卵黄囊内脏内胚层细胞缺乏大的顶端空泡。这些研究结果表明,Iqsec1 在胚胎发生过程中发挥着关键作用,很可能是通过调节内脏内胚层细胞的膜运输。
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引用次数: 0
FBXO46 negatively regulates p53 activity by stabilizing Mdm2. FBXO46 通过稳定 Mdm2 负向调节 p53 的活性。
IF 3.5 4区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-11-15 DOI: 10.1002/1873-3468.15055
Lai Wei, Ning Yu, Bo Yao, Yide Mei, Kailiang Zhao

The tumor suppressor p53 plays a central role in suppressing tumor formation. Mouse double minute 2 homolog (Mdm2) serves as the principal ubiquitin E3 ligase responsible for the ubiquitination and subsequent degradation of p53. However, the regulatory mechanisms governing the Mdm2-p53 pathway are not comprehensively understood. Here, we report that F-box only protein 46 (FBXO46) directly binds to Mdm2 and inhibits its self-ubiquitination and degradation, leading to Mdm2 stabilization and subsequent Mdm2-mediated ubiquitination and degradation of p53. Functionally, FBXO46 promotes cell proliferation, accelerates G1/S cell cycle progression, and increases anchorage-independent cell growth by inhibiting p53. Collectively, these findings reveal a critical role for FBXO46 in controlling Mdm2 stability and establish FBXO46 as an important regulator of the Mdm2-p53 pathway.

肿瘤抑制因子 p53 在抑制肿瘤形成方面发挥着核心作用。小鼠双分 2 同源物(Mdm2)是负责泛素化和随后降解 p53 的主要泛素 E3 连接酶。然而,Mdm2-p53 通路的调控机制尚未得到全面了解。在这里,我们报告了 F-box only 蛋白 46(FBXO46)直接与 Mdm2 结合并抑制其自我泛素化和降解,从而导致 Mdm2 的稳定和随后 Mdm2 介导的 p53 泛素化和降解。在功能上,FBXO46 通过抑制 p53 促进细胞增殖,加速 G1/S 细胞周期的进展,并增加锚定依赖性细胞的生长。总之,这些发现揭示了 FBXO46 在控制 Mdm2 稳定性中的关键作用,并确定 FBXO46 是 Mdm2-p53 通路的重要调节因子。
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引用次数: 0
The E3 ligase HUWE1 interacts with ubiquitin non-covalently via key residues in the HECT domain. E3 连接酶 HUWE1 通过 HECT 结构域中的关键残基与泛素进行非共价相互作用。
IF 3.5 4区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-11-14 DOI: 10.1002/1873-3468.15050
Li Sun, Haoran Zhang, Yan Li

HUWE1, a HECT E3 ligase, is critical for processes like protein degradation and tumor development. Contrary to previous findings which suggested minimal non-covalent interactions between the HUWE1 HECT domain and ubiquitin, we identified a non-covalent interaction between the HUWE1 HECT N-lobe and ubiquitin using NMR spectroscopy, revealing a conserved ubiquitin-binding mode shared across HECT E3 ligases. Molecular dynamics simulations not only confirmed the stability of this interaction but also uncovered conformational changes in key residues, which likely influence binding affinity. Additionally, we highlighted the roles of both conserved and unique residues in ubiquitin binding. These findings advance our understanding of the interactions between the HUWE1 HECT domain and ubiquitin, and highlight potential targets for therapeutic intervention in the ubiquitin-proteasome pathway.

HUWE1 是一种 HECT E3 连接酶,对蛋白质降解和肿瘤发展等过程至关重要。以前的研究结果表明,HUWE1 HECT结构域与泛素之间的非共价相互作用极少,与此相反,我们利用核磁共振光谱鉴定了HUWE1 HECT N-lobe与泛素之间的非共价相互作用,揭示了HECT E3连接酶共有的保守泛素结合模式。分子动力学模拟不仅证实了这种相互作用的稳定性,还发现了可能影响结合亲和力的关键残基的构象变化。此外,我们还强调了保守残基和独特残基在泛素结合中的作用。这些发现加深了我们对 HUWE1 HECT 结构域与泛素之间相互作用的理解,并突出了泛素-蛋白酶体途径中潜在的治疗干预靶点。
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引用次数: 0
Crystal structure of β-d-galactofuranosidase from Streptomyces sp. JHA19 in complex with an inhibitor provides insights into substrate specificity. 来自链霉菌 JHA19 的β-d-半乳糖呋喃糖苷酶与抑制剂复合物的晶体结构揭示了底物的特异性。
IF 3.5 4区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-11-14 DOI: 10.1002/1873-3468.15056
Noriki Fujio, Chihaya Yamada, Toma Kashima, Emiko Matsunaga, Robert J Nash, Kaoru Takegawa, Shinya Fushinobu

d-Galactofuranose (Galf) is widely distributed in glycoconjugates of pathogenic microbes. β-d-Galactofuranosidase (Galf-ase) from Streptomyces sp. JHA19 (ORF1110) belongs to glycoside hydrolase (GH) family 2 and is the first identified Galf-specific degradation enzyme. Here, the crystal structure of ORF1110 in complex with a mechanism-based potent inhibitor, d-iminogalactitol (Ki = 65 μm) was solved. ORF1110 binds to the C5-C6 hydroxy groups of d-iminogalactitol with an extensive and integral hydrogen bond network, a key interaction that discriminates the substrates. The active site structure of ORF1110 is largely different from those of β-glucuronidases and β-galactosidases in the same GH2 family. A C-terminal domain of ORF1110 is predicted to be a carbohydrate-binding module family 42 that may bind Galf. The structural insights into Galf-ase will contribute to the investigation of therapeutic tools against pathogens.

d-半乳糖呋喃糖(Galf)广泛分布于病原微生物的糖类共轭物中。来自链霉菌 JHA19(ORF1110)的β-d-半乳糖呋喃糖苷酶(Galf-ase)属于糖苷水解酶(GH)家族 2,是第一个被发现的 Galf 特异性降解酶。本研究解析了 ORF1110 与基于机制的强效抑制剂 d-iminogalactitol (Ki = 65 μm)的晶体结构。ORF1110 与 d-iminogalactitol 的 C5-C6 羟基结合,形成了一个广泛而完整的氢键网络,这是区分底物的关键相互作用。ORF1110 的活性位点结构在很大程度上不同于同属 GH2 家族的 β-葡萄糖醛酸酶和β-半乳糖苷酶。据预测,ORF1110 的 C 端结构域是可能与 Galf 结合的碳水化合物结合模块家族 42。对 Galf 酶结构的深入研究将有助于研究针对病原体的治疗工具。
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引用次数: 0
High-throughput detection of RNA modifications at single base resolution. 以单碱基分辨率高通量检测 RNA 修饰。
IF 3.5 4区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-11-14 DOI: 10.1002/1873-3468.15052
Keren Ron, Joshua Kahn, Nofar Malka-Tunitsky, Aldema Sas-Chen

RNA is modified by > 170 chemical modifications that affect its structure and function. Accordingly, RNA modifications have been implicated in regulation of gene expression and cellular outcomes in a variety of species spanning the phylogenetic tree. The study of RNA modifications is accelerated by generation of high-throughput methods for detecting RNA modifications at single base resolution. Here, we review recent advancement in next generation sequencing based approaches for detection of 14 distinct RNA modifications present in rRNA, tRNA and mRNA. We further outline the molecular and computational principles underlying currently available methods.

RNA 可通过 > 170 种化学修饰进行修饰,从而影响其结构和功能。因此,RNA 修饰与跨越系统发育树的各种物种的基因表达和细胞结果的调控有关。以单碱基分辨率检测 RNA 修饰的高通量方法的产生加速了对 RNA 修饰的研究。在此,我们回顾了基于新一代测序方法检测 rRNA、tRNA 和 mRNA 中 14 种不同 RNA 修饰的最新进展。我们进一步概述了目前可用方法的分子和计算原理。
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引用次数: 0
A guide for blood-brain barrier models. 血脑屏障模型指南
IF 3.5 4区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-11-12 DOI: 10.1002/1873-3468.15053
Yomna Soliman, Jana Al-Khodor, Gülnaz Yildirim Köken, Nur Mustafaoglu

Understanding the intricate mechanisms underlying brain-related diseases hinges on unraveling the pivotal role of the blood-brain barrier (BBB), an essential dynamic interface crucial for maintaining brain equilibrium. This review offers a comprehensive analysis of BBB physiology, delving into its cellular and molecular components while exploring a wide range of in vivo and in vitro BBB models. Notably, recent advancements in 3D cell culture techniques are explicitly discussed, as they have significantly improved the fidelity of BBB modeling by enabling the replication of physiologically relevant environments under flow conditions. Special attention is given to the cellular aspects of in vitro BBB models, alongside discussions on advances in stem cell technologies, providing valuable insights into generating robust cellular systems for BBB modeling. The diverse array of cell types used in BBB modeling, depending on their sources, is meticulously examined in this comprehensive review, scrutinizing their respective derivation protocols and implications. By synthesizing diverse approaches, this review sheds light on the improvements of BBB models to capture physiological conditions, aiding in understanding BBB interactions in health and disease conditions to foster clinical developments.

血脑屏障(BBB)是维持大脑平衡的重要动态界面,了解大脑相关疾病的复杂机制取决于揭示血脑屏障的关键作用。这篇综述全面分析了血脑屏障的生理学,深入研究了其细胞和分子成分,同时探讨了各种体内和体外血脑屏障模型。值得注意的是,本文明确讨论了三维细胞培养技术的最新进展,因为这些技术能够在流动条件下复制生理相关环境,从而大大提高了 BBB 模型的保真度。论文特别关注体外 BBB 模型的细胞方面,同时还讨论了干细胞技术的进展,为 BBB 建模提供了生成稳健细胞系统的宝贵见解。本综述细致研究了用于 BBB 建模的各种细胞类型(取决于它们的来源),仔细探讨了它们各自的衍生方案和影响。通过综合各种方法,本综述揭示了如何改进 BBB 模型以捕捉生理条件,从而帮助理解 BBB 在健康和疾病条件下的相互作用,促进临床开发。
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引用次数: 0
Glu592 of the axon guidance receptor ROBO3 mediates a pH-dependent interaction with NELL2 ligand. 轴突导向受体 ROBO3 的 Glu592 介导了与 NELL2 配体的 pH 依赖性相互作用。
IF 3.5 4区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-11-12 DOI: 10.1002/1873-3468.15054
Kimihiko Mizutani, Mayuko Toyoda, Teruyo Ojima-Kato, Andrés D Maturana, Tomoaki Niimi

There are only a few studies on the function of neuronal axon guidance molecules during low brain pH conditions. We previously reported that roundabout (ROBO) 2, a receptor for the axon guidance molecule SLIT, can bind to the neural epidermal growth factor-like-like (NELL) ligands in acidic conditions by conformational change of its ectodomain. Here, we show that the ROBO3 receptor also exhibits a pH-dependent increase in binding to the NELL2 ligand. We found that the Glu592 residue of ROBO3 at the binding interface between NELL2 and ROBO3 is a pH sensor and that the formation of a new hydrogen bonding network, due to protonation of the Glu592, leads to increased binding in acidic conditions. These results suggest that NELL2-ROBO3 signaling could be regulated by extracellular pH.

关于低脑pH值条件下神经元轴突导向分子功能的研究为数不多。我们以前曾报道,轴突导向分子SLIT的受体Roundabout(ROBO)2能在酸性条件下通过其外显子构象变化与神经表皮生长因子样(NELL)配体结合。在这里,我们发现 ROBO3 受体在与 NELL2 配体结合时也会出现 pH 依赖性增加。我们发现,在 NELL2 与 ROBO3 的结合界面上,ROBO3 的 Glu592 残基是一个 pH 传感器,由于 Glu592 的质子化,形成了一个新的氢键网络,从而导致在酸性条件下的结合增加。这些结果表明,NELL2-ROBO3的信号传导可能受细胞外pH值的调节。
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引用次数: 0
FoxO1 signaling in B cell malignancies and its therapeutic targeting. B 细胞恶性肿瘤中的 FoxO1 信号转导及其治疗靶点。
IF 3.5 4区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-11-12 DOI: 10.1002/1873-3468.15057
Krystof Hlavac, Petra Pavelkova, Laura Ondrisova, Marek Mraz

FoxO transcription factors (FoxO1, FoxO3a, FoxO4, FoxO6) are a highly evolutionary conserved subfamily of the 'forkhead' box proteins. They have traditionally been considered tumor suppressors, but FoxO1 also exhibits oncogenic properties. The complex nature of FoxO1 is illustrated by its various roles in B cell development and differentiation, immunoglobulin gene rearrangement and cell-surface B cell receptor (BCR) structure, DNA damage control, cell cycle regulation, and germinal center reaction. FoxO1 is tightly regulated at a transcriptional (STAT3, HEB, EBF, FoxOs) and post-transcriptional level (Akt, AMPK, CDK2, GSK3, IKKs, JNK, MAPK/Erk, SGK1, miRNA). In B cell malignancies, recurrent FoxO1 activating mutations (S22/T24) and aberrant nuclear export and activity have been described, underscoring the potential of its therapeutic inhibition. Here, we review FoxO1's roles across B cell and myeloid malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and multiple myeloma (MM). We also discuss preclinical evidence for FoxO1 targeting by currently available inhibitors (AS1708727, AS1842856, cpd10).

FoxO 转录因子(FoxO1、FoxO3a、FoxO4、FoxO6)是 "叉头 "盒蛋白亚家族中一个高度进化保守的亚家族。它们历来被认为是肿瘤抑制因子,但 FoxO1 也具有致癌特性。FoxO1 在 B 细胞发育和分化、免疫球蛋白基因重排和细胞表面 B 细胞受体(BCR)结构、DNA 损伤控制、细胞周期调控和生殖中心反应中的各种作用说明了 FoxO1 的复杂性。FoxO1 在转录水平(STAT3、HEB、EBF、FoxOs)和转录后水平(Akt、AMPK、CDK2、GSK3、IKKs、JNK、MAPK/Erk、SGK1、miRNA)受到严格调控。在 B 细胞恶性肿瘤中,FoxO1 的活化突变(S22/T24)和异常核输出及活性反复出现,这突显了其治疗抑制的潜力。在此,我们回顾了 FoxO1 在 B 细胞和髓系恶性肿瘤中的作用,即急性淋巴细胞白血病(ALL)、急性髓系白血病(AML)、慢性淋巴细胞白血病(CLL)、滤泡性淋巴瘤(FL)、弥漫大 B 细胞淋巴瘤(DLBCL)、套细胞淋巴瘤(MCL)、伯基特淋巴瘤(BL)、霍奇金淋巴瘤(HL)和多发性骨髓瘤(MM)。我们还讨论了目前可用的抑制剂(AS1708727、AS1842856、cpd10)靶向 FoxO1 的临床前证据。
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引用次数: 0
Cordycepin generally inhibits growth factor signal transduction in a systems pharmacology study. 在一项系统药理学研究中,虫草素通常会抑制生长因子信号转导。
IF 3.5 4区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-11-07 DOI: 10.1002/1873-3468.15046
Steven Lawrence, Jialiang Lin, Asma Khurshid, Wahyu Utami, Richa Singhania, Sadaf Ashraf, Graeme J Thorn, Irengbam Rocky Mangangcha, Keith Spriggs, Dong-Hyun Kim, David Barrett, Cornelia H de Moor

Cordycepin (3' deoxyadenosine) has been widely researched as a potential cancer therapy, but many diverse mechanisms of action have been proposed. Here, we confirm that cordycepin triphosphate is likely to be the active metabolite of cordycepin and that it consistently represses growth factor-induced gene expression. Bioinformatic analysis, quantitative PCR and western blotting confirmed that cordycepin blocks the PI3K/AKT/mTOR and/or MEK/ERK pathways in six cell lines and that AMPK activation is not required. The effects of cordycepin on translation through mTOR pathway repression were detectable within 30 min, indicating a rapid process. These data therefore indicate that cordycepin has a universal mechanism of action, acting as cordycepin triphosphate on an as yet unknown target molecule involved in growth factor signalling.

虫草素(3'脱氧腺苷)作为一种潜在的癌症疗法已被广泛研究,但人们提出了许多不同的作用机制。在这里,我们证实虫草素三磷酸酯可能是虫草素的活性代谢产物,而且它能持续抑制生长因子诱导的基因表达。生物信息学分析、定量 PCR 和 Western 印迹证实,虫草素在六种细胞系中阻断了 PI3K/AKT/mTOR 和/或 MEK/ERK 通路,而不需要激活 AMPK。通过抑制 mTOR 通路,虫草素对翻译的影响在 30 分钟内就能被检测到,表明这是一个快速的过程。因此,这些数据表明,虫草素具有一种普遍的作用机制,它以三磷酸虫草素的形式作用于参与生长因子信号传导的未知靶分子。
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引用次数: 0
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