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Roles of Kdm6a and Kdm6b in regulation of mammalian neural regeneration. X染色体编码的组蛋白去甲基化酶UTX通过微小RNA-124调节哺乳动物轴突再生。
Pub Date : 2024-10-01 DOI: 10.1101/2023.09.12.557354
Shu-Guang Yang, Xue-Wei Wang, Chang-Ping Li, Tao Huang, Cheng Qian, Qiao Li, Lingrui Zhao, Si-Yu Zhou, Saijilafu, Chang-Mei Liu, Feng-Quan Zhou

Epigenetic regulation of neuronal transcriptomic landscape is emerging to be a key coordinator of mammalian neural regeneration. Here we investigated roles of two histone 3 lysine 27 (H3K27) demethylases Kdm6a/b in controlling neuroprotection and axon regeneration. Deleting either Kdm6a or Kdm6b led to enhanced sensory axon regeneration in PNS, whereas in the CNS only deleting Kdm6a in retinal ganglion cells (RGCs) significantly enhanced optic nerve regeneration. Moreover, both Kdm6a and Kdm6b functioned to regulate RGC survival but with different mechanisms. Mechanistically, Kdm6a regulates RGC regeneration via distinct pathway from that of Pten and co-deleting Kdm6a and Pten resulted in long distance optic nerve regeneration passing the optic chiasm. In addition, RNA-seq profiling revealed that Kdm6a deletion switched the RGC transcriptomics into a developmental-like state and suppressed several known repressors of neural regeneration. Klf4 was identified as a direct downstream target of Kdm6a-H3K27me3 signaling in both sensory neurons and RGCs to regulate axon regeneration. These findings not only revealed different roles of Kdm6a and Kdm6b in regulation of neural regeneration and their underlying mechanisms, but also identified Kdm6a-mediated histone demethylation signaling as a novel epigenetic target for supporting CNS neural regeneration.

哺乳动物中枢神经系统(CNS)中的神经元在成熟过程中逐渐失去其固有的再生能力,主要是因为转录谱的改变。最近的研究通过鉴定可以被操纵以增强中枢神经系统再生的基因取得了巨大进展。然而,作为一个涉及许多基因和信号网络的复杂过程,破译潜在的神经元染色质和转录组景观协调中枢神经系统再生具有重要意义。在这里,我们鉴定了UTX,一种编码组蛋白去甲基化酶的X染色体相关基因,作为哺乳动物神经再生的新调节因子。我们证明UTX是外周神经系统(PNS)中自发轴突再生的阻遏物。在中枢神经系统中,敲除或药理学抑制视网膜神经节细胞(RGCs)中的UTX可显著增强神经元存活和视神经再生。RNA-seq图谱显示,删除UTX将RGC转录组转换为发育样状态。此外,微小RNA-124是成熟神经元中最丰富的微小RNA之一,被鉴定为UTX的下游靶点,阻断内源性微小RNA124-5p可导致强大的视神经再生。这些发现揭示了一种新的组蛋白修饰微小RNA表观遗传学信号网络,该网络协调支持中枢神经系统神经再生的转录组学景观。
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引用次数: 0
Unraveling Axonal Transcriptional Landscapes: Insights from iPSC-Derived Cortical Neurons and Implications for Motor Neuron Degeneration. 揭示轴突转录景观:iPSC 衍生皮质神经元的启示及对运动神经元退化的影响
Pub Date : 2024-10-01 DOI: 10.1101/2024.03.26.586780
Jishu Xu, Michaela Hörner, Maike Nagel, Perwin Perhat, Milena Korneck, Marvin Noß, Stefan Hauser, Ludger Schöls, Jakob Admard, Nicolas Casadei, Rebecca Schüle

Neuronal function and pathology are deeply influenced by the distinct molecular profiles of the axon and soma. Traditional studies have often overlooked these differences due to the technical challenges of compartment specific analysis. In this study, we employ a robust RNA-sequencing (RNA-seq) approach, using microfluidic devices, to generate high-quality axonal transcriptomes from iPSC-derived cortical neurons (CNs). We achieve high specificity of axonal fractions, ensuring sample purity without contamination. Comparative analysis revealed a unique and specific transcriptional landscape in axonal compartments, characterized by diverse transcript types, including protein-coding mRNAs, RNAs encoding ribosomal proteins (RPs), mitochondrial-encoded RNAs, and long non-coding RNAs (lncRNAs). Previous works have reported the existence of transcription factors (TFs) in the axon. Here, we detect a set of TFs specific to the axon and indicative of their active participation in transcriptional regulation. To investigate transcripts and pathways essential for central motor neuron (MN) degeneration and maintenance we analyzed KIF1C-knockout (KO) CNs, modeling hereditary spastic paraplegia (HSP), a disorder associated with prominent length-dependent degeneration of central MN axons. We found that several key factors crucial for survival and health were absent in KIF1C-KO axons, highlighting a possible role of these also in other neurodegenerative diseases. Taken together, this study underscores the utility of microfluidic devices in studying compartment-specific transcriptomics in human neuronal models and reveals complex molecular dynamics of axonal biology. The impact of KIF1C on the axonal transcriptome not only deepens our understanding of MN diseases but also presents a promising avenue for exploration of compartment specific disease mechanisms.

神经元的功能和病理深受轴突和体节不同分子特征的影响。由于区室特异性分析的技术挑战,传统研究往往忽略了这些差异。在这项研究中,我们利用微流体设备,采用稳健的 RNA 序列分析(RNA-seq)方法,从 iPSC 衍生的皮质神经元(CN)中生成高质量的轴突转录组。我们实现了轴突部分的高特异性,确保了样本的纯度而不受污染。比较分析表明,轴突区系中存在独特而特异的转录景观,其特征是转录本类型多样,包括编码蛋白质的mRNA、核糖体蛋白(RP)、线粒体编码的RNA和长非编码RNA(lncRNA)。以前的研究曾报道轴突中存在转录因子(TFs)。在这里,我们检测到了以前未报道过的轴突特异性 TFs 子集,这表明它们积极参与了转录调控。为了研究中枢运动神经元(MN)变性和维持所必需的转录本和通路,我们分析了KIF1C基因敲除(KO)的中枢运动神经元,模拟了遗传性痉挛性截瘫(HSP),这是一种与中枢运动神经元轴突突出的长度依赖性变性有关的疾病。我们发现,KIF1C-KO轴突中缺乏对生存和健康至关重要的几个关键因子,这表明这些因子在其他神经退行性疾病中也可能发挥作用。总之,这项研究强调了微流控设备在人类神经元模型中研究区室特异性转录组学的实用性,并揭示了轴突生物学复杂的分子动态。KIF1C 对轴突转录组的影响不仅加深了我们对多发性神经元疾病的理解,而且为探索特定区室的疾病机理提供了一个前景广阔的途径。
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引用次数: 0
A multiprotein signaling complex sustains AKT and mTOR/S6K activity necessary for the survival of cancer cells undergoing stress. Dock7调节癌症细胞转化表型和存活所需的AKT和mTOR/S6K活性。
Pub Date : 2024-10-01 DOI: 10.1101/2023.01.03.522657
Oriana Y Teran Pumar, Matthew R Zanotelli, Miao-Chong Joy Lin, Rebecca R Schmitt, Kai Su Green, Katherine S Rojas, Irene Y Hwang, Richard A Cerione, Kristin F Wilson

The ability of cancer cells to survive microenvironmental stresses is critical for tumor progression and metastasis; however, how they survive these challenges is not fully understood. Here, we describe a novel multiprotein complex (DockTOR) essential for the survival of cancer cells under stress, triggered by the GTPase Cdc42 and a signaling partner Dock7, which includes AKT, mTOR, and the mTOR regulators TSC1, TSC2, and Rheb. DockTOR enables cancer cells to maintain a low but critical mTORC2-dependent phosphorylation of AKT during serum deprivation by preventing AKT dephosphorylation through an interaction between phospho-AKT and the Dock7 DHR1 domain. This activity stimulates a Raptor-independent but Rapamycin-sensitive mTOR/S6K activity necessary for survival. These findings address long-standing questions of how Cdc42 signals result in mTOR activation and demonstrate how cancer cells survive conditions when growth factor-dependent activation of mTORC1 is off. Determining how cancer cells survive stress conditions could identify vulnerabilities that lead to new therapeutic strategies.

癌症细胞,无论是在发展中的肿瘤内还是在转移扩散过程中,都会遇到许多压力,需要适应机制才能生存和维持恶性进展。在这里,我们描述了一种涉及小GTP酶Cdc42和Dock7的信号复合物,一种Cdc42/Rac GEF和独特的Cdc42效应物,它在血清饥饿期间调节AKT、mTOR和其他mTOR信号和调节伙伴(包括TSC1/TCS2复合物和S6K)中具有以前未被重视的作用。Dock7在三阴性乳腺癌中高度表达,对于几种癌症细胞系在营养缺乏的生长条件下的恶性特性至关重要。我们发现Dock7与磷酸化AKT相互作用,以维持在营养胁迫期间生存所需的雷帕霉素敏感性和猛禽非依赖性mTORC1样活性的低但关键的激活。从癌症细胞敲除Dock7后,AKT和磷酸酶PHLPP之间的相互作用增加,而AKT在Ser473的磷酸化减少,这表明Dock7保护AKT免受去磷酸化。Dock7的DHR1结构域以前功能未知,通过需要其C2样基序的相互作用,负责在血清饥饿期间维持AKT Ser473磷酸化。总之,这些发现表明,Dock7保护并维持AKT的磷酸化,以维持癌症细胞中对失巢细胞的抵抗所必需的紧张性mTOR/S6K活性,并防止它们在应激条件下发生凋亡。
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引用次数: 0
Predicting the Sequence-Dependent Backbone Dynamics of Intrinsically Disordered Proteins. 预测本质无序蛋白质的序列依赖性主链动力学。
Pub Date : 2024-10-01 DOI: 10.1101/2023.02.02.526886
Sanbo Qin, Huan-Xiang Zhou

How the sequences of intrinsically disordered proteins (IDPs) code for functions is still an enigma. Dynamics, in particular residue-specific dynamics, holds crucial clues. Enormous efforts have been spent to characterize residue-specific dynamics of IDPs, mainly through NMR spin relaxation experiments. Here we present a sequence-based method, SeqDYN, for predicting residue-specific backbone dynamics of IDPs. SeqDYN employs a mathematical model with 21 parameters: one is a correlation length and 20 are the contributions of the amino acids to slow dynamics. Training on a set of 45 IDPs reveals aromatic, Arg, and long-branched aliphatic amino acids as the most active in slow dynamics whereas Gly and short polar amino acids as the least active. SeqDYN predictions not only provide an accurate and insightful characterization of sequence-dependent IDP dynamics but may also serve as indicators in a host of biophysical processes, including the propensities of IDP sequences to undergo phase separation.

动力学是内在无序蛋白质(IDP)序列和功能之间的关键联系。核磁共振自旋弛豫是表征IDP序列相关骨架动力学的一种强大技术。特别令人感兴趣的是15N横向弛豫率(R2),它报告了较慢的动力学(10s至1μs及以上)。NMR和分子动力学(MD)模拟表明,局部相互作用和二级结构的形成减缓了主链动力学并提高了R2。R2升高被认为是膜缔合、液-液相分离和其他功能过程的倾向性的指标。在这里,我们提出了一种基于序列的方法,SeqDYN,用于预测IDPs的R2。残基的R2值表示为所有残基的促成因子的乘积,这些促成因子随着与中心残基的序列距离的增加而减弱。该数学模型有21个参数,表示20种氨基酸的相关长度(其中衰减为50%)和贡献因子的幅度。对一组45个IDP的训练揭示了5.6个残基的相关长度,芳香族和长支链脂族氨基酸和Arg作为R2启动子,而Gly和短极性氨基酸作为R2抑制剂。SeqDYN的预测精度与最近使用IDP特定力场的MD模拟相比具有竞争力。对于结构化蛋白质,SeqDYN预测表示R2处于未折叠状态。SeqDYN可作为web服务器在https://zhougroup-uic.github.io/SeqDYNidp/用于快速R2预测。
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引用次数: 0
Mycolactone causes destructive Sec61-dependent loss of the endothelial glycocalyx and vessel basement membrane: a new indirect mechanism driving tissue necrosis in Mycobacterium ulcerans infection. 霉内酯导致内皮糖盏和基底膜的灾难性Sec61依赖性损失:溃疡分枝杆菌感染中导致组织坏死的一种新的间接机制。
Pub Date : 2024-10-01 DOI: 10.1101/2023.02.21.529382
Louise Tzung-Harn Hsieh, Belinda S Hall, Jane Newcombe, Tom A Mendum, Sonia Santana-Varela, Yagnesh Umrania, Michael J Deery, Wei Q Shi, Josué Diaz-Delgado, Francisco J Salguero, Rachel E Simmonds

The drivers of tissue necrosis in Mycobacterium ulcerans infection (Buruli ulcer disease) have historically been ascribed solely to the directly cytotoxic action of the diffusible exotoxin, mycolactone. However, its role in the clinically-evident vascular component of disease aetiology remains poorly explained. We have now dissected mycolactone's effects on primary vascular endothelial cells in vitro and in vivo. We show that mycolactone-induced changes in endothelial morphology, adhesion, migration, and permeability are dependent on its action at the Sec61 translocon. Unbiased quantitative proteomics identified a profound effect on proteoglycans, driven by rapid loss of type II transmembrane proteins of the Golgi, including enzymes required for glycosaminoglycan (GAG) synthesis, combined with a reduction in the core proteins themselves. Loss of the glycocalyx is likely to be of particular mechanistic importance, since knockdown of galactosyltransferase II (beta-1,3-galactotransferase 6; B3GALT6), the GAG linker-building enzyme, phenocopied the permeability and phenotypic changes induced by mycolactone. Additionally, mycolactone depleted many secreted basement membrane components and microvascular basement membranes were disrupted in vivo. Remarkably, exogenous addition of laminin-511 reduced endothelial cell rounding, restored cell attachment and reversed the defective migration caused by mycolactone. Hence supplementing mycolactone-depleted extracellular matrix may be a future therapeutic avenue, to improve wound healing rates.

溃疡分枝杆菌感染(布鲁里溃疡病)中组织坏死的驱动因素历来仅归因于可扩散外毒素分枝杆菌内酯的直接细胞毒性作用。然而,它在疾病病因的临床明显血管成分中的作用仍然没有得到很好的解释。我们现在已经在体外和体内解剖了霉内酯对原代血管内皮细胞的影响。我们发现,霉内酯诱导的内皮形态、粘附、迁移和通透性的变化取决于其在Sec61易位中的作用。无偏定量蛋白质组学确定了对蛋白聚糖的深刻影响,这是由高尔基体II型跨膜蛋白的快速损失驱动的,包括糖胺聚糖(GAG)合成所需的酶,再加上核心蛋白本身的减少。糖盏的损失可能具有特别重要的机制,因为敲低半乳糖基转移酶II(β-1,3-半乳糖转移酶6;B3Galt6),即GAG接头构建酶,表型复制了霉内酯诱导的渗透性和表型变化。此外,霉内酯耗尽了许多分泌的基底膜成分,微血管基底膜在体内被破坏。值得注意的是,外源性添加层粘连蛋白-511减少了内皮细胞的圆形化,恢复了细胞附着,并逆转了霉内酯引起的缺陷迁移。因此,补充缺乏霉内酯的细胞外基质可能是未来提高伤口愈合率的治疗途径。
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引用次数: 0
STING induces HOIP-mediated synthesis of M1 ubiquitin chains to stimulate NFκB signaling. STING诱导LUBAC介导的线性泛素链的合成以刺激先天免疫信号传导。
Pub Date : 2024-10-01 DOI: 10.1101/2023.10.14.562349
Tara D Fischer, Eric N Bunker, Peng-Peng Zhu, François Le Guerroué, Mahan Hadjian, Eunice Dominguez-Martin, Francesco Scavone, Robert Cohen, Tingting Yao, Yan Wang, Achim Werner, Richard J Youle

STING activation by cyclic dinucleotides in mammals induces IRF3- and NFκB -mediated gene expression, and the lipidation of LC3B at Golgi-related membranes. While mechanisms of the IRF3 response are well understood, the mechanisms of NFκB activation mediated by STING remain unclear. We report that STING activation induces linear/M1-linked ubiquitin chain (M1-Ub) formation and recruitment of the LUBAC E3 ligase, HOIP, to LC3B-associated Golgi membranes where ubiquitin is also localized. Loss of HOIP prevents formation of M1-Ub ubiquitin chains and reduces STING-induced NFκB and IRF3-mediated signaling in human monocytic THP1 cells and mouse bone marrow derived macrophages, without affecting STING activation. STING-induced LC3B lipidation is not required for M1-Ub chain formation or the immune-related gene expression, however the recently reported function of STING to neutralize the pH of the Golgi may be involved. Thus, LUBAC synthesis of M1 ubiquitin chains mediates STING-induced innate immune signaling.

哺乳动物中环状二核苷酸对STING的激活诱导干扰素和NFκB相关基因的表达,以及高尔基体膜LC3B的脂质化。虽然干扰素反应的机制已经很清楚,但STING介导的NFκB活化的机制仍不清楚。我们报道STING激活诱导LC3B相关高尔基体膜上K63-和M1连接/线性泛素链的形成。LUBAC E3泛素连接酶的缺失可阻止线性但非K63连接的泛素链的形成或STING的激活,并抑制单核细胞THP1细胞中STING诱导的NFκB和IRF3介导的信号传导。STING的质子通道活性对K63和线性泛素链的形成以及NFκB-和干扰素相关基因的表达也很重要。因此,线性泛素链的LUBAC合成调节STING介导的先天免疫信号传导。
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引用次数: 0
A systematic comparison of computational methods for expression forecasting. 表情预测计算方法的系统比较。
Pub Date : 2024-10-01 DOI: 10.1101/2023.07.28.551039
Eric Kernfeld, Yunxiao Yang, Joshua Weinstock, Alexis Battle, Patrick Cahan

Expression forecasting methods use machine learning models to predict how a cell will alter its transcriptome upon perturbation. Such methods are enticing because they promise to answer pressing questions in fields ranging from developmental genetics to cell fate engineering and because they are a fast, cheap, and accessible complement to the corresponding experiments. However, the absolute and relative accuracy of these methods is poorly characterized, limiting their informed use, their improvement, and the interpretation of their predictions. To address these issues, we created a benchmarking platform that combines a panel of 11 large-scale perturbation datasets with an expression forecasting software engine that encompasses or interfaces to a wide variety of methods. We used our platform to systematically assess methods, parameters, and sources of auxiliary data, finding that performance strongly depends on the choice of metric, and especially for simple metrics like mean squared error, it is uncommon for expression forecasting methods to out-perform simple baselines. Our platform will serve as a resource to improve methods and to identify contexts in which expression forecasting can succeed.

由于单细胞RNA-seq数据丰富,最近发表了许多预测扰动后表达的方法。表达预测方法之所以吸引人,是因为它们有望回答从发育遗传学到细胞命运工程等领域的紧迫问题,而且它们比实验方法更快、更便宜、产量更高。然而,这些方法的绝对和相对准确性特征不佳,限制了它们的知情使用、改进和对其预测的解释。为了解决这些问题,我们创建了一个基准测试平台,该平台将大规模扰动数据集面板与包含或接口当前方法的表达式预测软件引擎相结合。我们使用我们的平台系统地评估方法、参数和辅助数据的来源。我们发现不知情的基线预测,并不总是包括在先前的评估中,在所有测试用例中产生与基准方法相同或更好的平均绝对误差。这些结果对当前表达预测方法提供机制见解或对实验后续假设进行排序的能力提出了质疑。然而,鉴于该领域的快速创新,新的方法可能会产生更准确的表达预测。我们的平台将作为一个中立的基准来改进方法,并确定表达预测可以成功的上下文。
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引用次数: 0
The AAA+ protein Msp1 recognizes substrates by a hydrophobic mismatch. AAA+ 蛋白质 Msp1 通过疏水错配识别底物。
Pub Date : 2024-09-29 DOI: 10.1101/2023.07.11.548587
Heidi L Fresenius, Deepika Gaur, Baylee Smith, Brian Acquaviva, Matthew L Wohlever

An essential aspect of protein quality control is enzymatic removal of membrane proteins from the lipid bilayer. Failures in this essential cellular process are associated with neurodegenerative diseases and cancer. Msp1 is a AAA+ (ATPases Associated with diverse cellular Activities) protein that removes mistargeted proteins from the outer mitochondrial membrane (OMM). How Msp1 selectively recognizes and extracts substrates within the complex OMM ecosystem, and the role of the lipid bilayer on these processes is unknown. Here, we describe the development of fully defined, rapid, and quantitative extraction assay that retains physiological substrate selectivity. Using this new assay, we systematically modified both substrates and the lipid environment to demonstrate that Msp1 recognizes substrates by a hydrophobic mismatch between the substrate TMD and the lipid bilayer. We further demonstrate that the rate limiting step in Msp1 activity is extraction of the TMD from the lipid bilayer. Together, these results provide foundational insights into how the lipid bilayer influences AAA+ mediated membrane protein extraction.

蛋白质质量控制的一个重要方面是通过酶从脂质双分子层中去除膜蛋白。这一重要细胞过程的失败与神经退行性疾病和癌症有关。Msp1 是一种 AAA+(与多种细胞活动有关的 ATPases)蛋白,它能从线粒体外膜(OMM)上清除目标错误的蛋白质。Msp1 如何在复杂的线粒体外膜生态系统中选择性地识别和提取底物,以及脂质双分子层在这些过程中的作用尚不清楚。在这里,我们描述了完全定义、快速和定量提取测定的发展,它保留了生理底物选择性。利用这种新的检测方法,我们系统地改变了底物和脂质环境,证明 Msp1 是通过底物 TMD 与脂质双分子层之间的疏水错配来识别底物的。我们进一步证明,Msp1 活性的限速步骤是从脂质双分子层中提取 TMD。这些结果为我们深入了解脂质双分子层如何影响 AAA+ 介导的膜蛋白提取提供了基础。
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引用次数: 0
Mitotic chromatin marking governs asymmetric segregation of DNA damage. 有丝分裂染色质标记控制DNA损伤的不对称分离。
Pub Date : 2024-09-28 DOI: 10.1101/2023.09.04.556166
Juliette Ferrand, Juliette Dabin, Odile Chevallier, Matteo Kane-Charvin, Ariana Kupai, Joel Hrit, Scott B Rothbart, Sophie E Polo

The faithful segregation of intact genetic material and the perpetuation of chromatin states through mitotic cell divisions are pivotal for maintaining cell function and identity across cell generations. However, most exogenous mutagens generate long-lasting DNA lesions that are segregated during mitosis. How this segregation is controlled is unknown. Here, we uncover a mitotic chromatin-marking pathway that governs the segregation of UV-induced damage in human cells. Our mechanistic analyses reveal two layers of control: histone ADP-ribosylation, and the incorporation of newly synthesized histones at UV damage sites, that both prevent local mitotic phosphorylations on histone H3 serine residues. Functionally, this chromatin-marking pathway drives the asymmetric segregation of UV damage in the cell progeny with consequences on daughter cell fate. We propose that this mechanism may help preserve the integrity of stem cell compartments during asymmetric cell divisions.

完整遗传物质的忠实分离和染色质状态通过有丝分裂细胞分裂的持久化对于在细胞世代中维持细胞功能和身份至关重要。然而,大多数外源性诱变剂会产生持久的DNA损伤,这些损伤在有丝分裂过程中被分离。这种隔离是如何控制的还不得而知。在这里,我们揭示了一种有丝分裂染色质标记途径,它控制着人类细胞中紫外线诱导损伤的分离。我们的机制分析揭示了两层控制:组蛋白ADP核糖基化和新合成的组蛋白在紫外线损伤位点的结合,这两层都可以防止组蛋白H3丝氨酸的局部有丝分裂磷酸化。从功能上讲,这种染色质标记途径驱动细胞子代中紫外线损伤的不对称分离,并对子细胞命运产生潜在影响。我们提出,这种机制可能有助于在不对称细胞分裂过程中保持干细胞区室的完整性。
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引用次数: 0
Structural prediction of chimeric immunogens to elicit targeted antibodies against betacoronaviruses. 嵌合免疫原引发针对β冠状病毒的靶向抗体的结构预测。
Pub Date : 2024-09-28 DOI: 10.1101/2023.01.31.526494
Jamel Simpson, Peter M Kasson

Betacoronaviruses pose an ongoing pandemic threat. Antigenic evolution of the SARS-CoV-2 virus has shown that much of the spontaneous antibody response is narrowly focused rather than broadly neutralizing against even SARS-CoV-2 variants, let alone future threats. One way to overcome this is by focusing the antibody response against better-conserved regions of the viral spike protein. Here, we present a design approach to predict stable chimeras between SARS-CoV-2 and other coronaviruses, creating synthetic spike proteins that display a desired conserved region and vary other regions. We leverage AlphaFold to predict chimeric structures and create a new metric for scoring chimera stability based on AlphaFold outputs. We evaluated 114 candidate spike chimeras using this approach. Top chimeras were further evaluated using molecular dynamics simulation as an intermediate validation technique, showing good stability compared to low-scoring controls. Experimental testing of five predicted-stable and two predicted-unstable chimeras confirmed 5/7 predictions, with one intermediate result. This demonstrates the feasibility of the underlying approach, which can be used to design custom immunogens to focus the immune response against a desired viral glycoprotein epitope.

Betacoronavirus构成了持续的流行病威胁。严重急性呼吸系统综合征冠状病毒2型病毒的抗原进化表明,大部分自发抗体反应都是狭隘的,而不是广泛中和,甚至可以对抗严重急性呼吸系冠状病毒2型变种,更不用说未来的威胁了。克服这一问题的一种方法是将抗体反应集中在病毒刺突蛋白的更好保守区域。在这里,我们提出了一种设计方法来预测严重急性呼吸系统综合征冠状病毒2型和其他冠状病毒之间的稳定嵌合体,创造出显示所需保守区域并改变其他区域的合成刺突蛋白。我们利用AlphaFold来预测嵌合结构,并基于AlphaFol德的输出创建了一个新的嵌合稳定性评分指标。我们使用这种方法评估了114个候选刺突嵌合体。使用分子动力学模拟作为中间验证技术对顶部嵌合体进行了进一步评估,与低评分对照相比显示出良好的稳定性。这证明了潜在方法的可行性,该方法可用于设计定制免疫原,以集中针对所需病毒糖蛋白表位的免疫反应。
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bioRxiv : the preprint server for biology
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