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Embryonic stem cells maintain high origin activity and slow forks to coordinate replication with cell cycle progression. 胚胎干细胞保持高起源活性和慢叉,以协调复制和细胞周期进展。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-07-25 DOI: 10.1038/s44319-024-00207-5
Kiminori Kurashima, Yasunao Kamikawa, Tomomi Tsubouchi

Embryonic stem (ES) cells are pluripotent stem cells that can produce all cell types of an organism. ES cells proliferate rapidly and are thought to experience high levels of intrinsic replication stress. Here, by investigating replication fork dynamics in substages of S phase, we show that mammalian pluripotent stem cells maintain a slow fork speed and high active origin density throughout the S phase, with little sign of fork pausing. In contrast, the fork speed of non-pluripotent cells is slow at the beginning of S phase, accompanied by increased fork pausing, but thereafter fork pausing rates decline and fork speed rates accelerate in an ATR-dependent manner. Thus, replication fork dynamics within the S phase are distinct between ES and non-ES cells. Nucleoside addition can accelerate fork speed and reduce origin density. However, this causes miscoordination between the completion of DNA replication and cell cycle progression, leading to genome instability. Our study indicates that fork slowing in the pluripotent stem cells is an integral aspect of DNA replication.

胚胎干细胞(ES)是多能干细胞,可产生生物体的所有细胞类型。ES细胞增殖迅速,被认为经历了高水平的内在复制压力。在这里,我们通过研究S期子阶段的复制叉动态,表明哺乳动物多能干细胞在整个S期保持缓慢的复制叉速度和较高的活性起源密度,几乎没有复制叉暂停的迹象。相反,非多能细胞的分叉速度在S期开始时很慢,伴随着分叉暂停的增加,但此后分叉暂停率下降,分叉速度以依赖ATR的方式加快。因此,ES细胞和非ES细胞在S期的复制叉动态是不同的。添加核苷可加快分叉速度并降低起源密度。然而,这会造成DNA复制完成与细胞周期进展之间的不协调,从而导致基因组不稳定。我们的研究表明,多能干细胞中的分叉速度减慢是DNA复制不可或缺的一个方面。
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引用次数: 0
Mucosal IFNλ1 mRNA-based immunomodulation effectively reduces SARS-CoV-2 induced mortality in mice. 基于粘膜 IFNλ1 mRNA 的免疫调节可有效降低 SARS-CoV-2 诱导的小鼠死亡率。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-07-26 DOI: 10.1038/s44319-024-00216-4
Anna Macht, Yiqi Huang, Line S Reinert, Vincent Grass, Kristin Lohmer, Elke Tatjana Aristizabal Prada, Eveline Babel, Alexandra Semmler, Wen Zhang, Andrea Wegner, Eva Lichtenegger-Hartl, Sonja Haas, Günther Hasenpusch, Steffen Meyer, Søren R Paludan, Andreas Pichlmair, Carsten Rudolph, Thomas Langenickel

RNA vaccines elicit protective immunity against SARS-CoV-2, but the use of mRNA as an antiviral immunotherapeutic is unexplored. Here, we investigate the activity of lipidoid nanoparticle (LNP)-formulated mRNA encoding human IFNλ1 (ETH47), which is a critical driver of innate immunity at mucosal surfaces protecting from viral infections. IFNλ1 mRNA administration promotes dose-dependent protein translation, induction of interferon-stimulated genes without relevant signs of unspecific immune stimulation, and dose-dependent inhibition of SARS-CoV-2 replication in vitro. Pulmonary administration of IFNλ1 mRNA in mice results in a potent reduction of virus load, virus-induced body weight loss and significantly increased survival. These data support the development of inhaled administration of IFNλ1 mRNA as a potential prophylactic option for individuals exposed to SARS-CoV-2 or at risk suffering from COVID-19. Based on the broad antiviral activity of IFNλ1 regardless of virus or variant, this approach might also be utilized for other respiratory viral infections or pandemic preparedness.

RNA 疫苗可引起对 SARS-CoV-2 的保护性免疫,但将 mRNA 用作抗病毒免疫疗法的研究尚属空白。在这里,我们研究了类脂纳米粒子(LNP)制备的编码人类 IFNλ1 (ETH47) 的 mRNA 的活性。IFNλ1 mRNA 的给药促进了剂量依赖性蛋白翻译,诱导了干扰素刺激基因,而没有相关的非特异性免疫刺激迹象,并在体外对 SARS-CoV-2 的复制产生了剂量依赖性抑制作用。通过肺部给小鼠注射 IFNλ1 mRNA 可有效减少病毒载量,减轻病毒引起的体重下降,并显著提高存活率。这些数据支持开发吸入给药 IFNλ1 mRNA,作为暴露于 SARS-CoV-2 或面临 COVID-19 风险的个体的潜在预防选择。基于 IFNλ1 广泛的抗病毒活性,无论病毒或变种如何,这种方法也可用于其他呼吸道病毒感染或大流行的防备。
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引用次数: 0
BCL-2 and BOK regulate apoptosis by interaction of their C-terminal transmembrane domains. BCL-2 和 BOK 通过其 C 端跨膜结构域的相互作用调节细胞凋亡。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-07-24 DOI: 10.1038/s44319-024-00206-6
Tobias B Beigl, Alexander Paul, Thomas P Fellmeth, Dang Nguyen, Lynn Barber, Sandra Weller, Benjamin Schäfer, Bernhard F Gillissen, Walter E Aulitzky, Hans-Georg Kopp, Markus Rehm, David W Andrews, Kristyna Pluhackova, Frank Essmann

The Bcl-2 family controls apoptosis by direct interactions of pro- and anti-apoptotic proteins. The principle mechanism is binding of the BH3 domain of pro-apoptotic proteins to the hydrophobic groove of anti-apoptotic siblings, which is therapeutically exploited by approved BH3-mimetic anti-cancer drugs. Evidence suggests that also the transmembrane domain (TMD) of Bcl-2 proteins can mediate Bcl-2 interactions. We developed a highly-specific split luciferase assay enabling the analysis of TMD interactions of pore-forming apoptosis effectors BAX, BAK, and BOK with anti-apoptotic Bcl-2 proteins in living cells. We confirm homotypic interaction of the BAX-TMD, but also newly identify interaction of the TMD of anti-apoptotic BCL-2 with the TMD of BOK, a peculiar pro-apoptotic Bcl-2 protein. BOK-TMD and BCL-2-TMD interact at the endoplasmic reticulum. Molecular dynamics simulations confirm dynamic BOK-TMD and BCL-2-TMD dimers and stable heterotetramers. Mutation of BCL-2-TMD at predicted key residues abolishes interaction with BOK-TMD. Also, inhibition of BOK-induced apoptosis by BCL-2 depends specifically on their TMDs. Thus, TMDs of Bcl-2 proteins are a relevant interaction interface for apoptosis regulation and provide a novel potential drug target.

Bcl-2 家族通过促凋亡蛋白和抗凋亡蛋白的直接相互作用来控制细胞凋亡。其主要机制是促凋亡蛋白的 BH3 结构域与抗凋亡同胞的疏水沟结合,已获批准的 BH3 拟态抗癌药物利用了这一机制。有证据表明,Bcl-2 蛋白的跨膜结构域(TMD)也能介导 Bcl-2 相互作用。我们开发了一种高度特异性的分离荧光素酶测定法,可以分析活细胞中孔形成凋亡效应物 BAX、BAK 和 BOK 与抗凋亡 Bcl-2 蛋白的 TMD 相互作用。我们证实了 BAX-TMD 的同型相互作用,还新发现了抗凋亡 BCL-2 的 TMD 与 BOK(一种特殊的促凋亡 Bcl-2 蛋白)的 TMD 之间的相互作用。BOK-TMD 和 BCL-2-TMD 在内质网上相互作用。分子动力学模拟证实了 BOK-TMD 和 BCL-2-TMD 的动态二聚体和稳定的异构四聚体。在预测的关键残基上突变 BCL-2-TMD,可消除与 BOK-TMD 的相互作用。此外,BCL-2 对 BOK 诱导的细胞凋亡的抑制作用特别依赖于它们的 TMD。因此,Bcl-2 蛋白的 TMD 是调节细胞凋亡的相关相互作用界面,并提供了一个新的潜在药物靶点。
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引用次数: 0
Ubiquitination of VE-cadherin regulates inflammation-induced vascular permeability in vivo. VE-cadherin的泛素化调节炎症诱导的体内血管通透性。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-08-07 DOI: 10.1038/s44319-024-00221-7
Markus Wilkens, Leonie Holtermann, Ann-Kathrin Stahl, Rebekka I Stegmeyer, Astrid F Nottebaum, Dietmar Vestweber

VE-cadherin is a major component of the cell adhesion machinery which provides integrity and plasticity of the barrier function of endothelial junctions. Here, we analyze whether ubiquitination of VE-cadherin is involved in the regulation of the endothelial barrier in inflammation in vivo. We show that histamine and thrombin stimulate ubiquitination of VE-cadherin in HUVEC, which is completely blocked if the two lysine residues K626 and K633 are replaced by arginine. Similarly, these mutations block histamine-induced endocytosis of VE-cadherin. We describe two knock-in mouse lines with endogenous VE-cadherin being replaced by either a VE-cadherin K626/633R or a VE-cadherin KallR mutant, where all seven lysine residues are mutated. Mutant mice are viable, healthy and fertile with normal expression levels of junctional VE-cadherin. Histamine- or LPS-induced vascular permeability in the skin or lung of both of these mutant mice are clearly and similarly reduced in comparison to WT mice. Additionally, we detect a role of K626/633 for lysosomal targeting. Collectively, our findings identify ubiquitination of VE-cadherin as important for the induction of vascular permeability in the inflamed skin and lung.

VE-cadherin是细胞粘附机制的一个主要组成部分,它提供了内皮连接屏障功能的完整性和可塑性。在此,我们分析了 VE-cadherin 泛素化是否参与了体内炎症中内皮屏障的调控。我们发现组胺和凝血酶会刺激 HUVEC 中 VE-cadherin 的泛素化,如果 K626 和 K633 这两个赖氨酸残基被精氨酸取代,泛素化就会被完全阻断。同样,这些突变也阻断了组胺诱导的 VE-cadherin 内吞。我们描述了两种基因敲入小鼠品系,内源性 VE-cadherin被 VE-cadherin K626/633R 或 VE-cadherin KallR 突变体所取代,其中所有七个赖氨酸残基都发生了突变。突变小鼠存活、健康、能育,交界处的 VE-cadherin表达水平正常。与 WT 小鼠相比,组胺或 LPS 诱导的血管通透性在这两种突变小鼠的皮肤或肺部都明显降低。此外,我们还发现了 K626/633 在溶酶体靶向中的作用。总之,我们的研究结果表明,VE-cadherin 的泛素化对诱导发炎皮肤和肺部的血管通透性非常重要。
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引用次数: 0
Satellite cell-derived TRIM28 is pivotal for mechanical load- and injury-induced myogenesis. 卫星细胞衍生的TRIM28对机械负荷和损伤诱导的肌肉生成至关重要。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-08-14 DOI: 10.1038/s44319-024-00227-1
Kuan-Hung Lin, Jamie E Hibbert, Corey Gk Flynn, Jake L Lemens, Melissa M Torbey, Nathaniel D Steinert, Philip M Flejsierowicz, Kiley M Melka, Garrison T Lindley, Marcos Lares, Vijayasaradhi Setaluri, Amy J Wagers, Troy A Hornberger

Satellite cells are skeletal muscle stem cells that contribute to postnatal muscle growth, and they endow skeletal muscle with the ability to regenerate after a severe injury. Here we discover that this myogenic potential of satellite cells requires a protein called tripartite motif-containing 28 (TRIM28). Interestingly, different from the role reported in a previous study based on C2C12 myoblasts, multiple lines of both in vitro and in vivo evidence reveal that the myogenic function of TRIM28 is not dependent on changes in the phosphorylation of its serine 473 residue. Moreover, the functions of TRIM28 are not mediated through the regulation of satellite cell proliferation or differentiation. Instead, our findings indicate that TRIM28 regulates the ability of satellite cells to progress through the process of fusion. Specifically, we discover that TRIM28 controls the expression of a fusogenic protein called myomixer and concomitant fusion pore formation. Collectively, the outcomes of this study expose the framework of a novel regulatory pathway that is essential for myogenesis.

卫星细胞是骨骼肌干细胞,有助于出生后的肌肉生长,它们赋予骨骼肌在严重损伤后再生的能力。在这里,我们发现卫星细胞的这种成肌潜能需要一种名为含三方基序 28(TRIM28)的蛋白质。有趣的是,与之前一项基于 C2C12 肌母细胞的研究中报道的作用不同,体外和体内的多种证据显示,TRIM28 的成肌功能并不依赖于其丝氨酸 473 残基的磷酸化变化。此外,TRIM28 的功能也不是通过调节卫星细胞的增殖或分化来实现的。相反,我们的研究结果表明,TRIM28 能够调节卫星细胞在融合过程中的进展。具体地说,我们发现 TRIM28 控制着一种叫做肌融合器的融合蛋白的表达以及随之而来的融合孔的形成。总之,这项研究的结果揭示了一种新的调控途径的框架,这种调控途径对肌形成至关重要。
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引用次数: 0
Ambassadors of peace : The anthropology of war and how to overcome the human killing instinct. 和平大使:战争人类学以及如何克服人类的杀戮本能。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-08-19 DOI: 10.1038/s44319-024-00231-5
Gian Paolo Dotto
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引用次数: 0
Retinoic acid-induced protein 14 links mechanical forces to Hippo signaling. 视黄酸诱导蛋白 14 将机械力与 Hippo 信号传递联系起来。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-08-19 DOI: 10.1038/s44319-024-00228-0
Wonyoung Jeong, Hyeryun Kwon, Sang Ki Park, In-Seob Lee, Eek-Hoon Jho

Cells sense and respond to various mechanical forces from the extracellular matrix primarily by modulating the actin cytoskeleton. Mechanical forces can be translated into biochemical signals in a process called mechanotransduction. Yes-associated protein (YAP) is an effector of Hippo signaling and a mediator of mechanotransduction, but how mechanical forces regulate Hippo signaling is still an open question. We propose that retinoic acid-induced protein 14 (RAI14) responds to mechanical forces and regulates Hippo signaling. RAI14 positively regulates the activity of YAP. RAI14 interacts with NF2, a key component of the Hippo pathway, and the interaction occurs on filamentous actin. When mechanical forces are kept low in cells, NF2 dissociates from RAI14 and filamentous actin, resulting in increased interactions with LATS1 and activation of the Hippo pathway. Clinical data show that tissue stiffness and expression of RAI14 and YAP are upregulated in tumor tissues and that RAI14 is strongly associated with adverse outcome in patients with gastric cancer. Our data suggest that RAI14 links mechanotransduction with Hippo signaling and mediates Hippo-related biological functions such as cancer progression.

细胞主要通过调节肌动蛋白细胞骨架来感知和响应来自细胞外基质的各种机械力。机械力可以在一个称为机械传导的过程中转化为生化信号。YAP(Yes-associated protein)是Hippo信号转导的效应因子,也是机械传导的介质,但机械力如何调节Hippo信号转导仍是一个未决问题。我们提出视黄酸诱导蛋白14(RAI14)对机械力做出反应并调节Hippo信号转导。RAI14 可正向调节 YAP 的活性。RAI14 与 Hippo 通路的关键成分 NF2 相互作用,这种作用发生在丝状肌动蛋白上。当细胞中的机械力保持在较低水平时,NF2 会从 RAI14 和丝状肌动蛋白上解离,从而增加与 LATS1 的相互作用并激活 Hippo 通路。临床数据显示,肿瘤组织中组织硬度和 RAI14 及 YAP 的表达上调,RAI14 与胃癌患者的不良预后密切相关。我们的数据表明,RAI14 将机械传导与 Hippo 信号转导联系起来,并介导 Hippo 相关的生物学功能,如癌症进展。
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引用次数: 0
Reversible acetylation of HDAC8 regulates cell cycle. HDAC8 的可逆乙酰化调节细胞周期。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-07-23 DOI: 10.1038/s44319-024-00210-w
Chaowei Sang, Xuedong Li, Jingxuan Liu, Ziyin Chen, Minhui Xia, Miao Yu, Wei Yu

HDAC8, a member of class I HDACs, plays a pivotal role in cell cycle regulation by deacetylating the cohesin subunit SMC3. While cyclins and CDKs are well-established cell cycle regulators, our knowledge of other regulators remains limited. Here we reveal the acetylation of K202 in HDAC8 as a key cell cycle regulator responsive to stress. K202 acetylation in HDAC8, primarily catalyzed by Tip60, restricts HDAC8 activity, leading to increased SMC3 acetylation and cell cycle arrest. Furthermore, cells expressing the mutant form of HDAC8 mimicking K202 acetylation display significant alterations in gene expression, potentially linked to changes in 3D genome structure, including enhanced chromatid loop interactions. K202 acetylation impairs cell cycle progression by disrupting the expression of cell cycle-related genes and sister chromatid cohesion, resulting in G2/M phase arrest. These findings indicate the reversible acetylation of HDAC8 as a cell cycle regulator, expanding our understanding of stress-responsive cell cycle dynamics.

HDAC8 是一类 HDAC 的成员,它通过对粘合素亚基 SMC3 进行去乙酰化,在细胞周期调控中发挥着关键作用。尽管细胞周期蛋白和CDK是公认的细胞周期调控因子,但我们对其他调控因子的了解仍然有限。在这里,我们揭示了 HDAC8 中 K202 的乙酰化是一种对应激做出反应的关键细胞周期调节因子。HDAC8 中的 K202 乙酰化主要由 Tip60 催化,它限制了 HDAC8 的活性,导致 SMC3 乙酰化增加和细胞周期停滞。此外,表达模拟 K202 乙酰化的 HDAC8 突变体形式的细胞显示出基因表达的显著变化,这可能与三维基因组结构的变化有关,包括染色体环相互作用的增强。K202 乙酰化会破坏细胞周期相关基因的表达和姐妹染色单体的内聚力,导致 G2/M 期停滞,从而影响细胞周期的进展。这些发现表明,HDAC8 的可逆乙酰化是一种细胞周期调控因子,拓展了我们对应激反应细胞周期动力学的认识。
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引用次数: 0
WIPI2b recruitment to phagophores and ATG16L1 binding are regulated by ULK1 phosphorylation. WIPI2b 招募到吞噬细胞和 ATG16L1 的结合受 ULK1 磷酸化的调控。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-08-16 DOI: 10.1038/s44319-024-00215-5
Andrea Gubas, Eleanor Attridge, Harold Bj Jefferies, Taki Nishimura, Minoo Razi, Simone Kunzelmann, Yuval Gilad, Thomas J Mercer, Michael M Wilson, Adi Kimchi, Sharon A Tooze

One of the key events in autophagy is the formation of a double-membrane phagophore, and many regulatory mechanisms underpinning this remain under investigation. WIPI2b is among the first proteins to be recruited to the phagophore and is essential for stimulating autophagy flux by recruiting the ATG12-ATG5-ATG16L1 complex, driving LC3 and GABARAP lipidation. Here, we set out to investigate how WIPI2b function is regulated by phosphorylation. We studied two phosphorylation sites on WIPI2b, S68 and S284. Phosphorylation at these sites plays distinct roles, regulating WIPI2b's association with ATG16L1 and the phagophore, respectively. We confirm WIPI2b is a novel ULK1 substrate, validated by the detection of endogenous phosphorylation at S284. Notably, S284 is situated within an 18-amino acid stretch, which, when in contact with liposomes, forms an amphipathic helix. Phosphorylation at S284 disrupts the formation of the amphipathic helix, hindering the association of WIPI2b with membranes and autophagosome formation. Understanding these intricacies in the regulatory mechanisms governing WIPI2b's association with its interacting partners and membranes, holds the potential to shed light on these complex processes, integral to phagophore biogenesis.

自噬的关键过程之一是形成双膜噬菌体,其背后的许多调控机制仍在研究之中。WIPI2b是最先被招募到吞噬体的蛋白质之一,它通过招募ATG12-ATG5-ATG16L1复合物、驱动LC3和GABARAP脂化来刺激自噬通量。在此,我们着手研究 WIPI2b 的功能如何受到磷酸化的调控。我们研究了 WIPI2b 上的两个磷酸化位点 S68 和 S284。这两个位点的磷酸化起着不同的作用,分别调节 WIPI2b 与 ATG16L1 和吞噬体的结合。通过检测 S284 的内源性磷酸化,我们证实 WIPI2b 是一种新型的 ULK1 底物。值得注意的是,S284位于18个氨基酸的伸展区内,当与脂质体接触时,会形成一个两性螺旋。S284 处的磷酸化破坏了两性螺旋的形成,阻碍了 WIPI2b 与膜的结合和自噬体的形成。了解 WIPI2b 与其相互作用伙伴和膜结合的复杂调控机制,有可能揭示吞噬细胞生物发生过程中不可或缺的这些复杂过程。
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引用次数: 0
Mandatory national language requirements in higher education. 高等教育中的强制性国家语言要求。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-07-18 DOI: 10.1038/s44319-024-00211-9
Shina Caroline Lynn Kamerlin
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引用次数: 0
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