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Local translatome sustains synaptic function in impaired Wallerian degeneration. 在沃勒里变性受损的情况下,局部转译体能维持突触功能。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-31 DOI: 10.1038/s44319-024-00301-8
Maria Paglione, Leonardo Restivo, Sarah Zakhia, Arnau Llobet Rosell, Marco Terenzio, Lukas J Neukomm

After injury, severed axons separated from their somas activate programmed axon degeneration, a conserved pathway to initiate their degeneration within a day. Conversely, severed projections deficient in programmed axon degeneration remain morphologically preserved with functional synapses for weeks to months after axotomy. How this synaptic function is sustained remains currently unknown. Here, we show that dNmnat overexpression attenuates programmed axon degeneration in distinct neuronal populations. Severed projections remain morphologically preserved for weeks. When evoked, they elicit a postsynaptic behavior, a readout for preserved synaptic function. We used ribosomal pulldown to isolate the translatome from these projections 1 week after axotomy. Translatome candidates of enriched biological classes identified by transcriptional profiling are validated in a screen using a novel automated system to detect evoked antennal grooming as a proxy for preserved synaptic function. RNAi-mediated knockdown reveals that transcripts of the mTORC1 pathway, a mediator of protein synthesis, and of candidate genes involved in protein ubiquitination and Ca2+ homeostasis are required for preserved synaptic function. Our translatome dataset also uncovers several uncharacterized Drosophila genes associated with human disease. It may offer insights into novel avenues for therapeutic treatments.

损伤后,与其体细胞分离的轴突会激活程序性轴突变性,这是一种在一天内启动轴突变性的保守途径。相反,缺乏程序性轴突变性的切断突起在轴突切断术后的数周至数月内仍能保持形态和功能性突触。这种突触功能是如何维持的目前仍是未知数。在这里,我们发现 dNmnat 的过表达能减轻不同神经元群的程序性轴突变性。被切断的神经投射在形态上可保持数周之久。当诱发时,它们会引起突触后行为,这是突触功能保留的读数。我们在轴突切断术一周后使用核糖体下拉法从这些突起中分离出转译体。通过转录谱分析确定的富集生物类别的转译组候选者在使用新型自动系统的筛选中得到验证,以检测诱发的触角梳理作为突触功能保留的替代物。通过 RNAi- 介导的基因敲除发现,蛋白合成介导因子 mTORC1 通路以及参与蛋白泛素化和 Ca2+ 平衡的候选基因的转录本是保留突触功能所必需的。我们的转译组数据集还发现了几个与人类疾病相关的未定性果蝇基因。它可能为新的治疗途径提供洞察力。
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引用次数: 0
The Dectin-1 and Dectin-2 clusters: C-type lectin receptors with fundamental roles in immunity. Dectin-1 和 Dectin-2 簇:在免疫中发挥重要作用的 C 型凝集素受体。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-31 DOI: 10.1038/s44319-024-00296-2
Mariano Malamud, Gordon D Brown

The ability of myeloid cells to recognize and differentiate endogenous or exogenous ligands rely on the presence of different transmembrane protein receptors. C-type lectin receptors (CLRs), defined by the presence of a conserved structural motif called C-type lectin-like domain (CTLD), are a crucial family of receptors involved in this process, being able to recognize a diverse range of ligands from glycans to proteins or lipids and capable of initiating an immune response. The Dectin-1 and Dectin-2 clusters involve two groups of CLRs, with genes genomically linked within the natural killer cluster of genes in both humans and mice, and all characterized by the presence of a single extracellular CTLD. Fundamental immune cell functions such as antimicrobial effector mechanisms as well as internalization and presentation of antigens are induced and/or regulated through activatory, or inhibitory signalling pathways triggered by these receptors after ligand binding. In this review, we will discuss the most recent concepts regarding expression, ligands, signaling pathways and functions of each member of the Dectin clusters of CLRs, highlighting the importance and diversity of their functions.

髓系细胞识别和分化内源性或外源性配体的能力依赖于不同跨膜蛋白受体的存在。C型凝集素受体(CLRs)由一个名为C型凝集素样结构域(CTLD)的保守结构基团定义,是参与这一过程的重要受体家族,能够识别从糖类到蛋白质或脂类的各种配体,并能启动免疫反应。Dectin-1和Dectin-2簇涉及两组CLR,其基因在人类和小鼠的自然杀伤基因簇中都有基因组联系,其特点都是存在单一的细胞外CTLD。免疫细胞的基本功能,如抗菌效应机制以及抗原的内化和呈递,都是在配体结合后通过这些受体触发的激活或抑制信号通路诱导和/或调节的。在这篇综述中,我们将讨论有关 CLRs Dectin 簇中每个成员的表达、配体、信号传导途径和功能的最新概念,强调其功能的重要性和多样性。
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引用次数: 0
Eicosapentaenoic acid induces macrophage Mox polarization to prevent diabetic cardiomyopathy. 二十碳五烯酸诱导巨噬细胞 Mox 极化以预防糖尿病心肌病。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-31 DOI: 10.1038/s44319-024-00271-x
Jie Li, Wenshan Nan, Xiaoli Huang, Huali Meng, Shue Wang, Yan Zheng, Ying Li, Hui Li, Zhiyue Zhang, Lei Du, Xiao Yin, Hao Wu

Diabetic cardiomyopathy (DC) leads to heart failure, with few effective approaches for its intervention. Eicosapentaenoic acid (EPA) is an essential nutrient that benefits the cardiovascular system, but its effect on DC remains unknown. Here, we report that EPA protects against DC in streptozotocin and high-fat diet-induced diabetic mice, with an emphasis on the reduction of cardiac M1-polarized macrophages. In vitro, EPA abrogates cardiomyocyte injury induced by M1-polarized macrophages, switching macrophage phenotype from M1 to Mox, but not M2, polarization. Moreover, macrophage Mox polarization combats M1-polarized macrophage-induced cardiomyocyte injury. Further, heme oxygenase 1 (HO-1) was identified to maintain the Mox phenotype, mediating EPA suppression of macrophage M1 polarization and the consequential cardiomyocyte injury. Mechanistic studies reveal that G-protein-coupled receptor 120 mediates the upregulation of HO-1 by EPA. Notably, EPA promotes Mox polarization in monocyte-derived macrophages from diabetic patients. The current study provides EPA and macrophage Mox polarization as novel strategies for DC intervention.

糖尿病心肌病(DC)会导致心力衰竭,但几乎没有有效的干预方法。二十碳五烯酸(EPA)是一种有益于心血管系统的必需营养素,但它对糖尿病心肌病的影响仍然未知。在这里,我们报告了 EPA 对链佐菌素和高脂饮食诱导的糖尿病小鼠的直流电有保护作用,重点是减少心脏 M1 极化巨噬细胞。在体外,EPA 可减轻 M1 极化巨噬细胞诱导的心肌细胞损伤,使巨噬细胞表型从 M1 极化转为 Mox 极化,而不是 M2 极化。此外,巨噬细胞的 Mox 极化还能对抗 M1 极化巨噬细胞诱导的心肌细胞损伤。此外,研究还发现血红素加氧酶1(HO-1)能维持Mox表型,介导EPA抑制巨噬细胞M1极化和随之而来的心肌细胞损伤。机理研究显示,G 蛋白偶联受体 120 介导了 EPA 对 HO-1 的上调。值得注意的是,EPA 能促进糖尿病患者单核巨噬细胞的 Mox 极化。目前的研究提供了 EPA 和巨噬细胞 Mox 极化作为直流电干预的新策略。
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引用次数: 0
Phosphorylation of P-stalk proteins defines the ribosomal state for interaction with auxiliary protein factors. P-stalk 蛋白的磷酸化决定了核糖体与辅助蛋白因子相互作用的状态。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-28 DOI: 10.1038/s44319-024-00297-1
Kamil Filipek, Sandra Blanchet, Eliza Molestak, Monika Zaciura, Colin Chih-Chien Wu, Patrycja Horbowicz-Drożdżal, Przemysław Grela, Mateusz Zalewski, Sebastian Kmiecik, Alan González-Ibarra, Dawid Krokowski, Przemysław Latoch, Agata L Starosta, Mateusz Mołoń, Yutian Shao, Lidia Borkiewicz, Barbara Michalec-Wawiórka, Leszek Wawiórka, Konrad Kubiński, Katarzyna Socała, Piotr Wlaź, Kyle W Cunningham, Rachel Green, Marina V Rodnina, Marek Tchórzewski

Ribosomal action is facilitated by the orchestrated work of trans-acting factors and ribosomal elements, which are subject to regulatory events, often involving phosphorylation. One such element is the ribosomal P-stalk, which plays a dual function: it activates translational GTPases, which support basic ribosomal functions, and interacts with the Gcn2 kinase, linking the ribosomes to the ISR pathway. We show that P-stalk proteins, which form a pentamer, exist in the cell exclusively in a phosphorylated state at five C-terminal domains (CTDs), ensuring optimal translation (speed and accuracy) and may play a role in the timely regulation of the Gcn2-dependent stress response. Phosphorylation of the CTD induces a structural transition from a collapsed to a coil-like structure, and the CTD gains conformational freedom, allowing specific but transient binding to various protein partners, optimizing the ribosome action. The report reveals a unique feature of the P-stalk proteins, indicating that, unlike most ribosomal proteins, which are regulated by phosphorylation in an on/off manner, the P-stalk proteins exist in a constantly phosphorylated state, which optimizes their interaction with auxiliary factors.

反式作用因子和核糖体元件的协调工作促进了核糖体的作用,而反式作用因子和核糖体元件受调控事件的影响,通常涉及磷酸化。核糖体 P-茎就是这样一种元素,它具有双重功能:激活支持核糖体基本功能的翻译 GTP 酶,并与 Gcn2 激酶相互作用,将核糖体与 ISR 途径连接起来。我们的研究表明,P-stalk 蛋白形成一个五聚体,在细胞中完全以五个 C 端结构域(CTD)的磷酸化状态存在,确保了最佳的翻译(速度和准确性),并可能在及时调节依赖 Gcn2 的应激反应中发挥作用。CTD 的磷酸化诱导结构从塌缩结构转变为线圈状结构,CTD 获得构象自由度,允许与各种蛋白质伙伴进行特异但短暂的结合,从而优化核糖体的作用。报告揭示了 P-茎蛋白的一个独特特征,表明与大多数核糖体蛋白通过磷酸化以开/关方式调节不同,P-茎蛋白处于持续磷酸化状态,从而优化了它们与辅助因子的相互作用。
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引用次数: 0
Human PC4 supports telomere stability and viability in cells utilizing the alternative lengthening of telomeres mechanism. 人类 PC4 利用端粒替代性延长机制支持端粒稳定性和细胞活力。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-28 DOI: 10.1038/s44319-024-00295-3
Sara Salgado, Patricia L Abreu, Beatriz Moleirinho, Daniela S Guedes, Lee Larcombe, Claus M Azzalin

Cancer cells with an activated Alternative Lengthening of Telomeres (ALT) mechanism elongate telomeres via homology-directed repair. Sustained telomeric replication stress is an essential trigger of ALT activity; however, it can lead to cell death if not properly restricted. By analyzing publicly available data from genome-wide CRISPR KO screenings, we have identified the multifunctional protein PC4 as a novel factor essential for ALT cell viability. Depletion of PC4 results in rapid ALT cell death, while telomerase-positive cells show minimal effects. PC4 depletion induces replication stress and telomere fragility primarily in ALT cells, and increases ALT activity. PC4 binds to telomeric DNA in cells, and its binding can be enhanced by telomeric replication stress. Finally, a mutant PC4 with partly impaired single stranded DNA binding activity is capable to localize to telomeres and suppress ALT activity and telomeric replication stress. We propose that PC4 supports ALT cell viability, at least partly, by averting telomere dysfunction. Further studies of PC4 interactions at ALT telomeres may hold promise for innovative therapies to eradicate ALT cancers.

激活了端粒替代性延长(ALT)机制的癌细胞会通过同源定向修复来延长端粒。持续的端粒复制压力是 ALT 活性的重要触发因素;但是,如果不加以适当限制,它可能会导致细胞死亡。通过分析从全基因组 CRISPR KO 筛选中公开获得的数据,我们发现多功能蛋白 PC4 是 ALT 细胞存活所必需的新型因子。消耗 PC4 会导致 ALT 细胞快速死亡,而端粒酶阳性细胞受到的影响最小。PC4 的耗竭主要会诱导 ALT 细胞的复制压力和端粒脆性,并增加 ALT 的活性。PC4 可与细胞中的端粒 DNA 结合,端粒复制压力可增强其结合力。最后,单链DNA结合活性部分受损的突变体PC4能够定位到端粒并抑制ALT活性和端粒复制压力。我们认为,PC4 至少部分地通过避免端粒功能障碍来支持 ALT 细胞的活力。进一步研究PC4在ALT端粒上的相互作用可能会为根除ALT癌症的创新疗法带来希望。
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引用次数: 0
CMTM3 regulates neutrophil activation and aggravates sepsis through TLR4 signaling. CMTM3 通过 TLR4 信号调节中性粒细胞的活化并加重败血症。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-25 DOI: 10.1038/s44319-024-00291-7
Haiyan Xue, Ziyan Xiao, Xiujuan Zhao, Shu Li, Qian Cheng, Chun Fu, Fengxue Zhu

Regulation of neutrophil activation plays a significant role in managing sepsis. CKLF-like MARVEL transmembrane domain containing (CMTM)3 is a membrane protein involved in immune response. Here, we find that CMTM3 expression is elevated in sepsis and plays a crucial role in mediating the imbalance of neutrophil migration. Cmtm3 knockout improves the survival rate of septic mice, mitigate inflammatory responses, and ameliorate organ damage. Mechanistically, the deletion of Cmtm3 reduced the expression of Toll-like receptor 4 (TLR4) on neutrophils, leading to a decrease in the expression of C-X-C motif chemokine receptor 2 (CXCR2) on the cell membrane. This resulted in a reduced migration of neutrophils from the bone marrow to the bloodstream, thereby attenuating their recruitment to vital organs. Our findings suggest that targeting CMTM3 holds promise as a therapeutic approach to ameliorate the dysregulation of neutrophil migration and multi-organ damage associated with sepsis.

中性粒细胞活化的调节在脓毒症的治疗中发挥着重要作用。CKLF-like MARVEL transmembrane domain containing (CMTM)3 是一种参与免疫反应的膜蛋白。在这里,我们发现 CMTM3 在脓毒症中表达升高,并在介导中性粒细胞迁移失衡方面起着至关重要的作用。Cmtm3基因敲除可提高脓毒症小鼠的存活率,减轻炎症反应和器官损伤。从机理上讲,Cmtm3 的缺失会降低中性粒细胞上 Toll 样受体 4(TLR4)的表达,从而导致细胞膜上 C-X-C motif 趋化因子受体 2(CXCR2)的表达减少。这导致中性粒细胞从骨髓向血液的迁移减少,从而减少了它们向重要器官的募集。我们的研究结果表明,以 CMTM3 为靶点有望成为一种治疗方法,改善脓毒症引起的中性粒细胞迁移失调和多器官损伤。
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引用次数: 0
Histone modifications and Sp1 promote GPR160 expression in bone cancer pain within rodent models. 在啮齿动物模型中,组蛋白修饰和 Sp1 可促进骨癌疼痛中 GPR160 的表达。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-24 DOI: 10.1038/s44319-024-00292-6
Chengfei Xu, Yahui Wang, Chaobo Ni, Miao Xu, Chengyu Yin, Qiuli He, Bing Ma, Jie Fu, Baoxia Zhao, Liping Chen, Tong Zhi, Shirong Wei, Liang Cheng, Hui Xu, Jiajun Xiao, Lei Yang, Qingqing Xu, Jiao Kuang, Boyi Liu, Qinghe Zhou, Xuewu Lin, Ming Yao, Huadong Ni

Bone cancer pain (BCP) affects ~70% of patients in advanced stages, primarily due to bone metastasis, presenting a substantial therapeutic challenge. Here, we profile orphan G protein-coupled receptors in the dorsal root ganglia (DRG) following tumor infiltration, and observe a notable increase in GPR160 expression. Elevated Gpr160 mRNA and protein levels persist from postoperative day 6 for over 18 days in the affected DRG, predominantly in small-diameter C-fiber type neurons specific to the tibia. Targeted interventions, including DRG microinjection of siRNA or AAV delivery, mitigate mechanical allodynia, cold, and heat hyperalgesia induced by the tumor. Tumor infiltration increases DRG neuron excitability in wild-type mice, but not in Gpr160 gene knockout mice. Tumor infiltration results in reduced H3K27me3 and increased H3K27ac modifications, enhanced binding of the transcription activator Sp1 to the Gpr160 gene promoter region, and induction of GPR160 expression. Modulating histone-modifying enzymes effectively alleviated pain behavior. Our study delineates a novel mechanism wherein elevated Sp1 levels facilitate Gpr160 gene transcription in nociceptive DRG neurons during BCP in rodents.

骨癌疼痛(BCP)影响着约 70% 的晚期患者,主要是由于骨转移所致,给治疗带来了巨大挑战。在这里,我们对肿瘤浸润后背根神经节(DRG)中的孤儿G蛋白偶联受体进行了分析,观察到GPR160的表达明显增加。Gpr160 mRNA和蛋白水平的升高从术后第6天开始在受影响的DRG中持续超过18天,主要存在于胫骨特异的小直径C纤维型神经元中。靶向干预(包括 DRG 显微注射 siRNA 或 AAV 传播)可减轻肿瘤诱导的机械异感、冷痛和热痛。肿瘤浸润会增加野生型小鼠的DRG神经元兴奋性,但不会增加Gpr160基因敲除小鼠的DRG神经元兴奋性。肿瘤浸润导致 H3K27me3 减少和 H3K27ac 修饰增加,转录激活剂 Sp1 与 Gpr160 基因启动子区域的结合增强,并诱导 GPR160 的表达。调节组蛋白修饰酶可有效缓解疼痛行为。我们的研究阐明了一种新的机制,即在啮齿类动物的 BCP 过程中,Sp1 水平的升高促进了痛觉 DRG 神经元中 Gpr160 基因的转录。
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引用次数: 0
Scientific truth: an endangered species. 科学真理:濒临灭绝的物种
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-24 DOI: 10.1038/s44319-024-00293-5
Frank Gannon
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引用次数: 0
The controversy around anti-amyloid antibodies for treating Alzheimer's disease : The European Medical Agency's ruling against the latest anti-amyloid drugs highlights the ongoing debate about their safety and efficacy. 围绕用于治疗阿尔茨海默病的抗淀粉样蛋白抗体的争议:欧洲医学机构针对最新抗淀粉样蛋白药物的规定凸显了对其安全性和有效性的持续争论。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-23 DOI: 10.1038/s44319-024-00294-4
Philip Hunter
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引用次数: 0
Targeting the transcription factor YY1 is synthetic lethal with loss of the histone demethylase KDM5C. 靶向转录因子 YY1 与组蛋白去甲基化酶 KDM5C 的缺失是合成致死的。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-21 DOI: 10.1038/s44319-024-00290-8
Qian Zheng, Pengfei Li, Yulong Qiang, Jiachen Fan, Yuzhu Xing, Ying Zhang, Fan Yang, Feng Li, Jie Xiong

An understanding of the enzymatic and scaffolding functions of epigenetic modifiers is important for the development of epigenetic therapies for cancer. The H3K4me2/3 histone demethylase KDM5C has been shown to regulate transcription. The diverse roles of KDM5C are likely determined by its interacting partners, which are still largely unknown. In this study, we screen for KDM5C-binding proteins and show that YY1 interacts with KDM5C. A synergistic antitumor effect is exerted when both KDM5C and YY1 are depleted, and targeting YY1 appears to be a vulnerability in KDM5C-deficient cancer cells. Mechanistically, KDM5C promotes global YY1 chromatin recruitment, especially at promoters. Moreover, an intact KDM5C JmjC domain but not KDM5C histone demethylase activity is required for KDM5C-mediated YY1 chromatin binding. Transcriptional profiling reveals that dual inhibition of KDM5C and YY1 increases transcriptional repression of cell cycle- and apoptosis-related genes. In summary, our work demonstrates a synthetic lethal interaction between YY1 and KDM5C and suggests combination therapies for cancer treatments.

了解表观遗传修饰因子的酶和支架功能对于开发癌症表观遗传疗法非常重要。H3K4me2/3组蛋白去甲基化酶KDM5C已被证明能调节转录。KDM5C 的多种作用可能是由其相互作用伙伴决定的,而这些伙伴在很大程度上还不为人所知。在这项研究中,我们筛选了 KDM5C 结合蛋白,结果表明 YY1 与 KDM5C 有相互作用。当KDM5C和YY1都被耗尽时,会产生协同抗肿瘤效应,而靶向YY1似乎是KDM5C缺陷癌细胞的一个弱点。从机理上讲,KDM5C 可促进 YY1 染色质的全局招募,尤其是在启动子处。此外,KDM5C介导的YY1染色质结合需要完整的KDM5C JmjC结构域,而非KDM5C组蛋白去甲基化酶活性。转录谱分析显示,KDM5C 和 YY1 的双重抑制增加了细胞周期和细胞凋亡相关基因的转录抑制。总之,我们的工作证明了 YY1 和 KDM5C 之间的合成致死相互作用,并提出了癌症治疗的组合疗法。
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引用次数: 0
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