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RNA degradation triggered by decapping is largely independent of initial deadenylation. 脱帽引发的 RNA 降解在很大程度上与最初的去淀粉化无关。
Pub Date : 2024-09-25 DOI: 10.1038/s44318-024-00250-x
Léna Audebert,Frank Feuerbach,Mostafa Zedan,Alexandra P Schürch,Laurence Decourty,Abdelkader Namane,Emmanuelle Permal,Karsten Weis,Gwenaël Badis,Cosmin Saveanu
RNA stability, important for eukaryotic gene expression, is thought to depend on deadenylation rates, with shortened poly(A) tails triggering decapping and 5' to 3' degradation. In contrast to this view, recent large-scale studies indicate that the most unstable mRNAs have, on average, long poly(A) tails. To clarify the role of deadenylation in mRNA decay, we first modeled mRNA poly(A) tail kinetics and mRNA stability in yeast. Independent of deadenylation rates, differences in mRNA decapping rates alone were sufficient to explain current large-scale results. To test the hypothesis that deadenylation and decapping are uncoupled, we used rapid depletion of decapping and deadenylation enzymes and measured changes in mRNA levels, poly(A) length and stability, both transcriptome-wide and with individual reporters. These experiments revealed that perturbations in poly(A) tail length did not correlate with variations in mRNA stability. Thus, while deadenylation may be critical for specific regulatory mechanisms, our results suggest that for most yeast mRNAs, it is not critical for mRNA decapping and degradation.
RNA 的稳定性对真核基因的表达非常重要,人们认为 RNA 的稳定性取决于去淀粉化率,缩短的 poly(A) 尾会触发去淀粉化和 5' 到 3' 的降解。与这种观点相反,最近的大规模研究表明,最不稳定的 mRNA 平均具有较长的 poly(A)尾。为了澄清脱烯酰化在 mRNA 降解中的作用,我们首先模拟了酵母中 mRNA 聚(A)尾动力学和 mRNA 的稳定性。独立于脱酶速率,mRNA 脱帽速率的差异本身就足以解释当前的大规模结果。为了验证去淀粉酰化和去淀粉酰化脱钩的假设,我们使用了快速去淀粉酰化和去淀粉酰化酶,并测量了整个转录组和单个报告基因的 mRNA 水平、poly(A) 长度和稳定性的变化。这些实验表明,poly(A) 尾长度的变化与 mRNA 稳定性的变化并不相关。因此,虽然去淀粉酰化可能对特定的调控机制至关重要,但我们的结果表明,对于大多数酵母 mRNA 而言,去淀粉酰化对 mRNA 的解帽和降解并不重要。
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引用次数: 0
Author Correction: PARP14 and PARP9/DTX3L regulate interferon-induced ADP-ribosylation. 作者更正:PARP14和PARP9/DTX3L调控干扰素诱导的ADP-核糖基化。
Pub Date : 2024-09-25 DOI: 10.1038/s44318-024-00247-6
Pulak Kar,Chatrin Chatrin,Nina Đukić,Osamu Suyari,Marion Schuller,Kang Zhu,Evgeniia Prokhorova,Nicolas Bigot,Domagoj Baretić,Juraj Ahel,Jonas Damgaard Elsborg,Michael L Nielsen,Tim Clausen,Sébastien Huet,Mario Niepel,Sumana Sanyal,Dragana Ahel,Rebecca Smith,Ivan Ahel
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引用次数: 0
m6A mRNA methylation by METTL14 regulates early pancreatic cell differentiation. METTL14 的 m6A mRNA 甲基化调控早期胰腺细胞分化。
Pub Date : 2024-09-25 DOI: 10.1038/s44318-024-00213-2
Sevim Kahraman,Dario F De Jesus,Jiangbo Wei,Natalie K Brown,Zhongyu Zou,Jiang Hu,Mehdi Pirouz,Richard I Gregory,Chuan He,Rohit N Kulkarni
N6-methyladenosine (m6A) is the most abundant chemical modification in mRNA and plays important roles in human and mouse embryonic stem cell pluripotency, maintenance, and differentiation. We have recently reported that m6A is involved in the postnatal control of β-cell function in physiological states and in type 1 and 2 diabetes. However, the precise mechanisms by which m6A acts to regulate the development of human and mouse pancreas are unexplored. Here, we show that the m6A landscape is dynamic during human pancreas development, and that METTL14, one of the m6A writer complex proteins, is essential for the early differentiation of both human and mouse pancreatic cells.
N6-甲基腺苷(m6A)是mRNA中最丰富的化学修饰,在人类和小鼠胚胎干细胞的全能性、维持和分化中发挥着重要作用。我们最近报告说,m6A 在生理状态和 1 型及 2 型糖尿病中参与了出生后对β细胞功能的控制。然而,m6A调控人类和小鼠胰腺发育的确切机制尚待探索。在这里,我们发现在人类胰腺发育过程中,m6A 的结构是动态的,而 m6A 作者复合蛋白之一 METTL14 对人类和小鼠胰腺细胞的早期分化至关重要。
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引用次数: 0
Toxin-mediated depletion of NAD and NADP drives persister formation in a human pathogen. 毒素介导的 NAD 和 NADP 消耗促使一种人类病原体形成顽固病菌。
Pub Date : 2024-09-25 DOI: 10.1038/s44318-024-00248-5
Isabella Santi,Raphael Dias Teixeira,Pablo Manfredi,Hector Hernandez Gonzalez,Daniel C Spiess,Guillaume Mas,Alexander Klotz,Andreas Kaczmarczyk,Nicola Zamboni,Sebastian Hiller,Urs Jenal
Toxin-antitoxin (TA) systems are widespread in bacteria and implicated in genome stability, virulence, phage defense, and persistence. TA systems have diverse activities and cellular targets, but their physiological roles and regulatory mechanisms are often unclear. Here, we show that the NatR-NatT TA system, which is part of the core genome of the human pathogen Pseudomonas aeruginosa, generates drug-tolerant persisters by specifically depleting nicotinamide dinucleotides. While actively growing P. aeruginosa cells compensate for NatT-mediated NAD+ deficiency by inducing the NAD+ salvage pathway, NAD depletion generates drug-tolerant persisters under nutrient-limited conditions. Our structural and biochemical analyses propose a model for NatT toxin activation and autoregulation and indicate that NatT activity is subject to powerful metabolic feedback control by the NAD+ precursor nicotinamide. Based on the identification of natT gain-of-function alleles in patient isolates and on the observation that NatT increases P. aeruginosa virulence, we postulate that NatT modulates pathogen fitness during infections. These findings pave the way for detailed investigations into how a toxin-antitoxin system can promote pathogen persistence by disrupting essential metabolic pathways.
毒素-抗毒素(TA)系统广泛存在于细菌中,并与基因组稳定性、毒力、噬菌体防御和持久性有关。TA 系统具有多种活性和细胞靶标,但其生理作用和调控机制往往并不清楚。在这里,我们展示了作为人类病原体铜绿假单胞菌核心基因组一部分的 NatR-NatT TA 系统,它通过特异性消耗烟酰胺二核苷酸产生耐药持久体。生长活跃的铜绿假单胞菌细胞会通过诱导 NAD+ 挽救途径来补偿 NatT 介导的 NAD+ 缺乏,而 NAD 消耗则会在营养受限的条件下产生耐药持久体。我们的结构和生化分析为 NatT 毒素的激活和自动调节提出了一个模型,并表明 NatT 的活性受到 NAD+ 前体烟酰胺的强大代谢反馈控制。根据在患者分离物中鉴定出的 NatT 功能增益等位基因以及 NatT 可提高铜绿假单胞菌毒力的观察结果,我们推测 NatT 可在感染过程中调节病原体的适应性。这些发现为详细研究毒素-抗毒素系统如何通过破坏重要的代谢途径来促进病原体的持续存在铺平了道路。
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引用次数: 0
BATokines in metabolic liver disease: good cops or bad cops? 代谢性肝病中的 BATokines:好警察还是坏警察?
Pub Date : 2024-09-25 DOI: 10.1038/s44318-024-00239-6
Renata O Pereira,E Dale Abel
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引用次数: 0
miRNA-mediated gene silencing in Drosophila larval development involves GW182-dependent and independent mechanisms. 果蝇幼虫发育过程中 miRNA 介导的基因沉默涉及 GW182 依赖性和独立机制。
Pub Date : 2024-09-25 DOI: 10.1038/s44318-024-00249-4
Eriko Matsuura-Suzuki,Kaori Kiyokawa,Shintaro Iwasaki,Yukihide Tomari
MicroRNAs (miRNAs) regulate a wide variety of biological processes by silencing their target genes. Argonaute (AGO) proteins load miRNAs to form an RNA-induced silencing complex (RISC), which mediates translational repression and/or mRNA decay of the targets. A scaffold protein called GW182 directly binds AGO and the CCR4-NOT deadenylase complex, initiating the mRNA decay reaction. Although previous studies have demonstrated the critical role of GW182 in cultured cells as well as in cell-free systems, its biological significance in living organisms remains poorly explored, especially in Drosophila melanogaster. Here, we generated gw182-null flies using the CRISPR/Cas9 system and found that, unexpectedly, they can survive until an early second-instar larval stage. Moreover, in vivo miRNA reporters can be effectively repressed in gw182-null first-instar larvae. Nevertheless, gw182-null flies have defects in the expression of chitin-related genes and the formation of the larval trachea system, preventing them from completing larval development. Our results highlight the importance of both GW182-dependent and -independent silencing mechanisms in vivo.
微小核糖核酸(miRNA)通过沉默靶基因调控多种生物过程。Argonaute (AGO) 蛋白加载 miRNA 形成 RNA 诱导的沉默复合体 (RISC),从而介导靶基因的翻译抑制和/或 mRNA 衰变。一种名为 GW182 的支架蛋白可直接结合 AGO 和 CCR4-NOT 死酶复合物,启动 mRNA 的衰减反应。尽管之前的研究已经证明了 GW182 在培养细胞和无细胞系统中的关键作用,但对其在生物体内的生物学意义,尤其是在黑腹果蝇中的生物学意义的探索仍然很少。在这里,我们利用 CRISPR/Cas9 系统生成了 gw182 缺失的果蝇,并意外地发现它们能存活到二龄幼虫早期。此外,体内 miRNA 报告也能在 gw182 缺失的一龄幼虫体内被有效抑制。然而,gw182-null蝇类在几丁质相关基因的表达和幼虫气管系统的形成方面存在缺陷,导致它们无法完成幼虫发育。我们的研究结果突显了体内依赖于 GW182 和不依赖于 GW182 的沉默机制的重要性。
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引用次数: 0
TBK1-Zyxin signaling controls tumor-associated macrophage recruitment to mitigate antitumor immunity. TBK1-Zyxin信号控制肿瘤相关巨噬细胞的招募,从而减轻抗肿瘤免疫。
Pub Date : 2024-09-20 DOI: 10.1038/s44318-024-00244-9
Ruyuan Zhou,Mengqiu Wang,Xiao Li,Yutong Liu,Yihan Yao,Ailian Wang,Chen Chen,Qian Zhang,Qirou Wu,Qi Zhang,Dante Neculai,Bing Xia,Jian-Zhong Shao,Xin-Hua Feng,Tingbo Liang,Jian Zou,Xiaojian Wang,Pinglong Xu
Mechanical control is fundamental for cellular localization within a tissue, including for tumor-associated macrophages (TAMs). While the innate immune sensing pathways cGAS-STING and RLR-MAVS impact the pathogenesis and therapeutics of malignant diseases, their effects on cell residency and motility remain incompletely understood. Here, we uncovered that TBK1 kinase, activated by cGAS-STING or RLR-MAVS signaling in macrophages, directly phosphorylates and mobilizes Zyxin, a key regulator of actin dynamics. Under pathological conditions and in STING or MAVS signalosomes, TBK1-mediated Zyxin phosphorylation at S143 facilitates rapid recruitment of phospho-Zyxin to focal adhesions, leading to subsequent F-actin reorganization and reduced macrophage migration. Intratumoral STING-TBK1-Zyxin signaling was evident in TAMs and critical in antitumor immunity. Furthermore, myeloid-specific or global disruption of this signaling decreased the population of CD11b+ F4/80+ TAMs and promoted PD-1-mediated antitumor immunotherapy. Thus, our findings identify a new biological function of innate immune sensing pathways by regulating macrophage tissue localization, thus providing insights into context-dependent mitigation of antitumor immunity.
机械控制是细胞(包括肿瘤相关巨噬细胞(TAMs))在组织内定位的基础。先天性免疫传感通路 cGAS-STING 和 RLR-MAVS 影响着恶性疾病的发病机制和治疗方法,但它们对细胞驻留和运动的影响仍不完全清楚。在这里,我们发现 TBK1 激酶在巨噬细胞中被 cGAS-STING 或 RLR-MAVS 信号激活后,会直接磷酸化并调动肌动蛋白动态的关键调节因子 Zyxin。在病理条件下,以及在 STING 或 MAVS 信号体中,TBK1 介导的 Zyxin 在 S143 处磷酸化可促进磷酸化 Zyxin 快速招募到焦点粘附处,从而导致随后的 F-肌动蛋白重组并减少巨噬细胞的迁移。瘤内 STING-TBK1-Zyxin 信号在 TAMs 中很明显,在抗肿瘤免疫中至关重要。此外,髓系特异性或全局性破坏这种信号传导会减少 CD11b+ F4/80+ TAMs 的数量,促进 PD-1 介导的抗肿瘤免疫疗法。因此,我们的研究结果发现了先天性免疫传感通路通过调节巨噬细胞组织定位的一种新的生物学功能,从而为抗肿瘤免疫的情境依赖性缓解提供了见解。
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引用次数: 0
A shorter splicing isoform antagonizes ZBP1 to modulate cell death and inflammatory responses. 一种较短的剪接异构体可拮抗 ZBP1,从而调节细胞死亡和炎症反应。
Pub Date : 2024-09-19 DOI: 10.1038/s44318-024-00238-7
Masahiro Nagata,Yasmin Carvalho Schäfer,Laurens Wachsmuth,Manolis Pasparakis
Z-DNA-binding protein 1 (ZBP1) is an interferon-inducible sensor of Z-DNA and Z-RNA, which has emerged as a critical regulator of cell death and inflammation. ZBP1 binds Z-DNA and Z-RNA via its Zα domains, and signals by engaging RIPK3 and RIPK1 via its RIP homotypic interaction motifs (RHIMs). Here, we show that mice express an alternatively-spliced shorter ZBP1 isoform (ZBP1-S), which harbours the Zα domains but lacks the RHIMs, and acts as an endogenous inhibitor of the full-length protein (ZBP1-L). Mice and cells expressing only ZBP1-S are resistant to ZBP1-mediated cell death and inflammation. In contrast, cells lacking ZBP1-S show increased ZBP1-L-induced death compared to cells expressing both isoforms. Moreover, loss of the short isoform accelerates and exacerbates skin inflammation induced by ZBP1-mediated necroptosis of RIPK1-deficient keratinocytes, revealing an important physiological role of ZBP1-S. Mechanistically, ZBP1-S suppresses ZBP1-L-mediated cell death by binding to Z-nucleic acids via its Zα domains. Therefore, ZBP1-S acts as an endogenous inhibitor that competes with full-length ZBP1-L for binding Z-nucleic acid ligands to fine-tune ZBP1-mediated cell death and inflammation.
Z-DNA结合蛋白1(ZBP1)是一种干扰素诱导的Z-DNA和Z-RNA传感器,它已成为细胞死亡和炎症的关键调节因子。ZBP1通过其Zα结构域结合Z-DNA和Z-RNA,并通过其RIP同型相互作用基序(RHIMs)与RIPK3和RIPK1结合发出信号。在这里,我们发现小鼠表达了一种交替剪接的较短 ZBP1 异构体(ZBP1-S),它含有 Zα 结构域但缺乏 RHIMs,可作为全长蛋白(ZBP1-L)的内源性抑制剂。仅表达 ZBP1-S 的小鼠和细胞对 ZBP1 介导的细胞死亡和炎症具有抵抗力。相反,与表达两种异构体的细胞相比,缺乏 ZBP1-S 的细胞显示 ZBP1-L 诱导的死亡增加。此外,短异构体的缺失会加速和加剧由 ZBP1 介导的 RIPK1 缺失型角质形成细胞坏死诱导的皮肤炎症,这揭示了 ZBP1-S 的重要生理作用。从机理上讲,ZBP1-S 通过其 Zα 结构域与 Z 核酸结合,从而抑制 ZBP1-L 介导的细胞死亡。因此,ZBP1-S 是一种内源性抑制剂,可与全长 ZBP1-L 竞争结合 Z 核酸配体,对 ZBP1 介导的细胞死亡和炎症进行微调。
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引用次数: 0
Astrocyte allocation during brain development is controlled by Tcf4-mediated fate restriction. 大脑发育过程中星形胶质细胞的分配受 Tcf4 介导的命运限制控制。
Pub Date : 2024-09-19 DOI: 10.1038/s44318-024-00218-x
Yandong Zhang,Dan Li,Yuqun Cai,Rui Zou,Yilan Zhang,Xin Deng,Yafei Wang,Tianxiang Tang,Yuanyuan Ma,Feizhen Wu,Yunli Xie
Astrocytes in the brain exhibit regional heterogeneity contributing to regional circuits involved in higher-order brain functions, yet the mechanisms controlling their distribution remain unclear. Here, we show that the precise allocation of astrocytes to specific brain regions during development is achieved through transcription factor 4 (Tcf4)-mediated fate restriction based on their embryonic origin. Loss of Tcf4 in ventral telencephalic neural progenitor cells alters the fate of oligodendrocyte precursor cells to transient intermediate astrocyte precursor cells, resulting in mislocalized astrocytes in the dorsal neocortex. These ectopic astrocytes engage with neocortical neurons and acquire features reminiscent of dorsal neocortical astrocytes. Furthermore, Tcf4 functions as a suppressor of astrocyte fate during the differentiation of oligodendrocyte precursor cells derived from the ventral telencephalon, thereby restricting the fate to the oligodendrocyte lineage in the dorsal neocortex. Together, our findings highlight a previously unappreciated role for Tcf4 in regulating astrocyte allocation, offering additional insights into the mechanisms underlying neurodevelopmental disorders linked to Tcf4 mutations.
大脑中的星形胶质细胞表现出区域异质性,有助于形成参与高阶大脑功能的区域回路,但控制其分布的机制仍不清楚。在这里,我们发现星形胶质细胞在发育过程中精确分配到特定脑区是通过转录因子 4(Tcf4)介导的基于胚胎起源的命运限制来实现的。腹侧端脑神经祖细胞中 Tcf4 的缺失改变了少突胶质细胞前体细胞到瞬时中间星形胶质细胞前体细胞的命运,导致星形胶质细胞在背侧新皮质中错位。这些异位星形胶质细胞与新皮质神经元接触,并获得与背侧新皮质星形胶质细胞相似的特征。此外,在源自腹侧端脑的少突胶质细胞前体细胞分化过程中,Tcf4 起着抑制星形胶质细胞命运的作用,从而限制了背侧新皮层少突胶质细胞系的命运。总之,我们的研究结果突显了 Tcf4 在调节星形胶质细胞分配方面以前未被认识到的作用,为了解与 Tcf4 基因突变相关的神经发育障碍的机制提供了新的视角。
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引用次数: 0
Acetylation of TIR domains in the TLR4-Mal-MyD88 complex regulates immune responses in sepsis. TLR4-Mal-MyD88复合物中TIR结构域的乙酰化调节败血症中的免疫反应。
Pub Date : 2024-09-18 DOI: 10.1038/s44318-024-00237-8
Xue Li,Xiangrong Li,Pengpeng Huang,Facai Zhang,Juanjuan K Du,Ying Kong,Ziqiang Shao,Xinxing Wu,Weijiao Fan,Houquan Tao,Chuanzan Zhou,Yan Shao,Yanling Jin,Meihua Ye,Yan Chen,Jong Deng,Jimin Shao,Jicheng Yue,Xiaju Cheng,Y Eugene Chinn
Activation of the Toll-like receptor 4 (TLR4) by bacterial endotoxins in macrophages plays a crucial role in the pathogenesis of sepsis. However, the mechanism underlying TLR4 activation in macrophages is still not fully understood. Here, we reveal that upon lipopolysaccharide (LPS) stimulation, lysine acetyltransferase CBP is recruited to the TLR4 signalosome complex leading to increased acetylation of the TIR domains of the TLR4 signalosome. Acetylation of the TLR4 signalosome TIR domains significantly enhances signaling activation via NF-κB rather than IRF3 pathways. Induction of NF-κB signaling is responsible for gene expression changes leading to M1 macrophage polarization. In sepsis patients, significantly elevated TLR4-TIR acetylation is observed in CD16+ monocytes combined with elevated expression of M1 macrophage markers. Pharmacological inhibition of HDAC1, which deacetylates the TIR domains, or CBP play opposite roles in sepsis. Our findings highlight the important role of TLR4-TIR domain acetylation in the regulation of the immune responses in sepsis, and we propose this reversible acetylation of TLR4 signalosomes as a potential therapeutic target for M1 macrophages during the progression of sepsis.
巨噬细胞中的细菌内毒素激活了 Toll 样受体 4(TLR4),这在败血症的发病机制中起着至关重要的作用。然而,巨噬细胞中 TLR4 的激活机制仍未完全明了。在这里,我们揭示了在脂多糖(LPS)刺激下,赖氨酸乙酰转移酶 CBP 被招募到 TLR4 信号体复合物中,导致 TLR4 信号体的 TIR 结构域乙酰化增加。TLR4 信号体 TIR 结构域的乙酰化显著增强了通过 NF-κB 而非 IRF3 途径激活信号的能力。NF-κB 信号的诱导是导致 M1 巨噬细胞极化的基因表达变化的原因。在败血症患者中,CD16+单核细胞中的TLR4-TIR乙酰化明显升高,同时M1巨噬细胞标志物的表达也升高。药理抑制 HDAC1(可使 TIR 结构域去乙酰化)或 CBP 在脓毒症中起着相反的作用。我们的研究结果突显了 TLR4-TIR 结构域乙酰化在调节脓毒症免疫反应中的重要作用,我们建议将 TLR4 信号体的这种可逆乙酰化作为脓毒症发展过程中 M1 巨噬细胞的潜在治疗靶点。
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引用次数: 0
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