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MAP4K4 regulates integrin-FERM binding to control endothelial cell motility
MAP4K4通过调节整合素-FERM的结合来控制内皮细胞的运动能力
http://www.nature.com/nature/journal/v519/n7544/full/nature14323.html
细胞迁移是一个渐次展开的过程，涉及到多种分子机制的协同作用。本研究组利用小干扰RNA和化学抑制剂，对体外血管形成过程进行了筛选，发现了一条MAP4K4-膜突蛋白-踝蛋白-整合素β1分子通路，它能有效促进内皮细胞迁移过程中质膜的回缩。MAP4K4的缺失会导致膜动态减弱、内皮细胞迁移变慢、血管形成过程（体内和体外）受损。在处于迁移过程的内皮细胞中，MAP4K4使处在焦点粘连解体处正在回缩的膜上的膜突蛋白磷酸化。上位性分析表明，膜突蛋白在MAP4K4的下游起作用，通过与踝蛋白竞争结合整合素β1的胞內域，使整合素失活。因此，膜突蛋白（由MSN基因编码）或MAP4K4的缺失会降低内皮细胞中粘附连接的解体速率。此外，整合素α5β1的阻断能逆转与MAP4K4相关的膜回缩缺陷（体内和体外）。本研究揭开了关于内皮细胞迁移研究的一个新角度。最后，MAP4K4功能缺陷能抑制疾病模型中的病理性血管形成，说明MAP4K4还有成为治疗靶标的潜力。
Regulated eukaryotic DNA replication origin firing with purified proteins
用纯化的蛋白质研究真核细胞DNA复制起始点的调节
http://www.nature.com/nature/journal/v519/n7544/full/nature14285.html
真核细胞的DNA复制是多起点式的，这就要求它要被严格控制，以保证每个细胞周期都能精确地完成基因组复制。为实现此目的，复制起始工程被分为两个在时间上分离的步骤：一个双重六聚小染色体维护（minichromosome maintenance，MCM）复合体在G1期首先进入复制起始点，随后在S期转化为激活的CMG（Cdc45-MCM-GINS）解旋酶。本文描述了用42个多肽构成的、16个纯化的复制因子进行的出芽酵母DNA复制起始过程的重建。起始点依赖性的起始过程重现了体内的调节。细胞周期蛋白依赖性激酶（CDK）通过磷酸化起始点识别复合物（origin recognition complex，ORC）来抑制MCM进入，通过磷酸化Sld2 和Sld3促进CMG形成。Dbf4-依赖性激酶（DDK）通过磷酸化MCM促进复制，并可在CDK之前或之后起作用。这些实验明确了调节真核DNA复制中需要的蛋白质、蛋白质激酶底物和辅因子的最小补充。
Two insulin receptors determine alternative wing morphs in planthoppers
两种胰岛素受体决定飞虱的翅型分化
http://www.nature.com/nature/journal/v519/n7544/full/nature14286.html
doi:10.1038/nature14286
翅的非遗传多型性，是一种在许多昆虫物种中发现的、进化上很成功的特征。长翅型昆虫擅长飞行，是故能更快地逃离不利的生境、或是追踪变化多端的资源；短翅型昆虫飞行能力很弱，但其繁殖能力往往更强。对于蚜虫、蟋蟀和飞虱的研究表明，同一物种内部的翅型分化是由环境因素的不同导致的。这种对不同环境因素的不同响应，可能是发育激素诱导的，然而究竟是何种激素在其中起作用，迄今为止的研究结果仍处在争论中。目前的情况是，昆虫翅型分化决定的分子机制尚不清楚。本文表明，迁移性褐飞虱（Nilaparvata lugens）的两个胰岛素受体——InR1和InR2——在通过调节叉头转录因子Foxo进而控制长短翅分化的过程中，起着截然相反的作用。InR1通过肌醇磷脂3激酶（PI（3）K）-蛋白质激酶B（Akt）信号通路，在活化时导致飞虱发育为长翅型，而在失活时导致飞虱发育为短翅型。与此相反，InR2的功能是负向调节InR1-PI（3）K-Akt通路，抑制InR2导致长翅型的产生。脑分泌的配体Ilp3能引发长翅型的发育。本文的发现为昆虫翅的非遗传多型性的分子调节机制打开了第一扇门，同时这也是在可变发育结果中首次发现的双向控制。因此，这些发现加深了人类对发育和表型可塑性演化的理解。
N6-methyladenosine marks primary microRNAs for processing
N6甲基腺嘌呤标记并促进初级microRNA加工
http://www.nature.com/nature/journal/v519/n7544/full/nature14281.html
形成成熟microRNA的第一步是microprocessor复合体介导加工初级microRNA (primary microRNA, pri-miRNAs) 。microprocessor复合体由RNA结合蛋白DGCR8和III型RNAase DROSHA组成。这个起始事件需要DGCR8识别RNA的茎环结构和侧翼相接的单链RNA之间的交叉点，并招募DROSHA，DROSHA能切断双链RNA、生成次级microRNA（pre-miRNA）。虽然现在pri-miRNA的机制已经阐述的很清楚了，但是DGCR8是如何识别并结合pri-miRNA、而不是转录本中的其他RNA二级结构，还不是很清楚。本研究组发现哺乳动物细胞甲基转移酶样3（methyltransferase-like 3，METTL3）能甲基化pri-miRNA，从而使之被DGCR8识别并结合。与其相一致的是，去除METTL3后，DGCR8结合pri-miRNA减少，导致了全局性的成熟miRNA的锐减，并伴随未加工的pri-miRNAs的积累。体外加工实验证实了N6甲基腺嘌呤足以促使pri-miRNA转化为成熟miRNA。最后，功能获得性实验（gain-of-function experiment）揭示了METTL3能在全局上促进miRNA的成熟，并且这种促进能力是无细胞类型特异性的。这些发现揭示了m6A标记在后转录修饰过程中，在促进miRNA合成起始方面扮演着重要的角色。
Structural imprints in vivo decode RNA regulatory mechanisms
体内RNA结构印记解密RNA调节机制
http://www.nature.com/nature/journal/v519/n7544/full/nature14263.html
可视化活细胞内分子行为的物理基础一直是生物学中的巨大挑战。RNA是生物调控中心分子，RNA采取特定结构的能力紧密地调控着基因表达的每一步。然而，对于RNA的生理结构我们还了解的不是很清楚。就目前来说，体内RNA结构谱仅仅包括组成RNA的四个核酸中两个。本文提供了一种新的生物化学方法——体内点击选择性2’-羟基酰化绘制图谱实验（in vivo click selective 2′-hydroxyl acylation and profiling experiment，icSHAPE），这种方法第一次打开了活细胞内基于全部四种核苷酸的RNA二级结构的全局视野。将小鼠胚胎干细胞转录本的icSHAPE结果跟纯化折叠的体外RNA相比后，本研究组发现，能通过细胞环境中RNA的结构动力学区分不同种类的RNA和调节元件。结构上的标志特征，如翻译起点和核糖体滞留位点，在体内外环境之间是保守的，暗示着这些RNA元件是由序列所“编码”的。相反，体内的聚焦结构重排揭示了RNA与RNA结合蛋白、RNA修饰位点之间的精确作用位点，这些同原子水平的分辨率结构数据是相一致的。利用这种动态的结构印记，研究者能准确预测RNA与蛋白的相互作用和全基因组范围的N6甲基腺嘌呤修饰。这些结果为活细胞的结构性RNA组研究打开了一个新的视野，并且揭示了控制基因表达的重要RNA生理结构。
hiCLIP reveals the in vivo atlas of mRNA secondary structures recognized by Staufen 1
通过hiCLIP揭示被Staufen 1识别的体内mRNA的二级结构图谱
http://www.nature.com/nature/journal/v519/n7544/full/nature14280.html
mRNA的结构对转录后调节很重要的原因在于，它能影响反式作用因子的结合。然而，人们对于体内全长mRNA的结构了解还很少。本文提供了一个生化技术——hiCLP——用来在全转录组水平上鉴别与RNA结合蛋白（RNA-binding proteins，RBPs）相互作用的RNA的二级结构。本研究组通过这种技术，在人类细胞中研究与Staufen 1（STAU1）结合的RNA的二级结构。本研究组发现，其中大部分RNA会形成分子内双链体；被大量翻译的mRNA的编码区很少参与双链体的形成；预料之外地，3’非翻译区（3′ untranslated regions，UTRs）上广泛存在大段的双链体；以及在双链体形成区域中单链核酸多态性的减少。本研究组还在X框结合蛋白（X-box binding protein 1，XBP1）mRNA的3’ UTR区域内发现一个横跨858核苷酸的双链体，该区域调节XBP1的mRNA在细胞内的剪接和稳定性。综上，本研究揭示了mRNA二级结构在基因表达过程中的重要作用，并引入hiCLIP作为一项可广泛应用发现新RNA二级结构的技术，尤其适用于大段的RNA二聚体。
Lineage correlations of single cell division time as a probe of cell-cycle dynamics
http://www.nature.com/nature/journal/v519/n7544/full/nature14318.html
Stochastic processes in cells are associated with fluctuations in mRNA, protein production and degradation, noisy partition of cellular components at division, and other cell processes. Variability within a clonal population of cells originates from such stochastic processes, which may be amplified or reduced by deterministic factors. Cell-to-cell variability, such as that seen in the heterogeneous response of bacteria to antibiotics, or of cancer cells to treatment, is understood as the inevitable consequence of stochasticity. Variability in cell-cycle duration was observed long ago; however, its sources are still unknown. A central question is whether the variance of the observed distribution originates from stochastic processes, or whether it arises mostly from a deterministic process that only appears to be random. A surprising feature of cell-cycle-duration inheritance is that it seems to be lost within one generation but to be still present in the next generation, generating poor correlation between mother and daughter cells but high correlation between cousin cells. This observation suggests the existence of underlying deterministic factors that determine the main part of cell-to-cell variability. We developed an experimental system that precisely measures the cell-cycle duration of thousands of mammalian cells along several generations and a mathematical framework that allows discrimination between stochastic and deterministic processes in lineages of cells. We show that the inter- and intra-generation correlations reveal complex inheritance of the cell-cycle duration. Finally, we build a deterministic nonlinear toy model for cell-cycle inheritance that reproduces the main features of our data. Our approach constitutes a general method to identify deterministic variability in lineages of cells or organisms, which may help to predict and, eventually, reduce cell-to-cell heterogeneity in various systems, such as cancer cells under treatment.
Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease
http://www.nature.com/nature/journal/v519/n7544/full/nature14332.html
Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric-oxide- and natriuretic-peptide-coupled signalling, stimulating phosphorylation changes by protein kinase G. Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease. However, cGMP stimulation alone is limited by counter-adaptions including PDE upregulation. Furthermore, although PDE5A regulates nitric-oxide-generated cGMP, nitric oxide signalling is often depressed by heart disease. PDEs controlling natriuretic-peptide-coupled cGMP remain uncertain. Here we show that cGMP-selective PDE9A is expressed in the mammalian heart, including humans, and is upregulated by hypertrophy and cardiac failure. PDE9A regulates natriuretic-peptide- rather than nitric-oxide-stimulated cGMP in heart myocytes and muscle, and its genetic or selective pharmacological inhibition protects against pathological responses to neurohormones, and sustained pressure-overload stress. PDE9A inhibition reverses pre-established heart disease independent of nitric oxide synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. Transcription factor activation and phosphoproteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to NOS activation. Thus, unlike PDE5A, PDE9A can regulate cGMP signalling independent of the nitric oxide pathway, and its role in stress-induced heart disease suggests potential as a therapeutic target.
SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1
http://www.nature.com/nature/journal/v519/n7544/full/nature14107.html
Cell growth and proliferation are tightly linked to nutrient availability. The mechanistic target of rapamycin complex 1 (mTORC1) integrates the presence of growth factors, energy levels, glucose and amino acids to modulate metabolic status and cellular responses. mTORC1 is activated at the surface of lysosomes by the RAG GTPases and the Ragulator complex through a not fully understood mechanism monitoring amino acid availability in the lysosomal lumen and involving the vacuolar H+-ATPase. Here we describe the uncharacterized human member 9 of the solute carrier family 38 (SLC38A9) as a lysosomal membrane-resident protein competent in amino acid transport. Extensive functional proteomic analysis established SLC38A9 as an integral part of the Ragulator–RAG GTPases machinery. Gain of SLC38A9 function rendered cells resistant to amino acid withdrawal, whereas loss of SLC38A9 expression impaired amino-acid-induced mTORC1 activation. Thus SLC38A9 is a physical and functional component of the amino acid sensing machinery that controls the activation of mTOR.
The paraventricular thalamus controls a central amygdala fear circuit
http://www.nature.com/nature/journal/v519/n7544/full/nature13978.html
Appropriate responses to an imminent threat brace us for adversities. The ability to sense and predict threatening or stressful events is essential for such adaptive behaviour. In the mammalian brain, one putative stress sensor is the paraventricular nucleus of the thalamus (PVT), an area that is readily activated by both physical and psychological stressors. However, the role of the PVT in the establishment of adaptive behavioural responses remains unclear. Here we show in mice that the PVT regulates fear processing in the lateral division of the central amygdala (CeL), a structure that orchestrates fear learning and expression. Selective inactivation of CeL-projecting PVT neurons prevented fear conditioning, an effect that can be accounted for by an impairment in fear-conditioning-induced synaptic potentiation onto somatostatin-expressing (SOM+) CeL neurons, which has previously been shown to store fear memory. Consistently, we found that PVT neurons preferentially innervate SOM+ neurons in the CeL, and stimulation of PVT afferents facilitated SOM+ neuron activity and promoted intra-CeL inhibition, two processes that are critical for fear learning and expression. Notably, PVT modulation of SOM+ CeL neurons was mediated by activation of the brain-derived neurotrophic factor (BDNF) receptor tropomysin-related kinase B (TrkB). As a result, selective deletion of either Bdnf in the PVT or Trkb in SOM+ CeL neurons impaired fear conditioning, while infusion of BDNF into the CeL enhanced fear learning and elicited unconditioned fear responses. Our results demonstrate that the PVT–CeL pathway constitutes a novel circuit essential for both the establishment of fear memory and the expression of fear responses, and uncover mechanisms linking stress detection in PVT with the emergence of adaptive behaviour.
A temporal shift in the circuits mediating retrieval of fear memory
http://www.nature.com/nature/journal/v519/n7544/full/nature14030.html
Fear memories allow animals to avoid danger, thereby increasing their chances of survival. Fear memories can be retrieved long after learning, but little is known about how retrieval circuits change with time. Here we show that the dorsal midline thalamus of rats is required for the retrieval of auditory conditioned fear at late (24 hours, 7 days, 28 days), but not early (0.5 hours, 6 hours) time points after learning. Consistent with this, the paraventricular nucleus of the thalamus (PVT), a subregion of the dorsal midline thalamus, showed increased c-Fos expression only at late time points, indicating that the PVT is gradually recruited for fear retrieval. Accordingly, the conditioned tone responses of PVT neurons increased with time after training. The prelimbic (PL) prefrontal cortex, which is necessary for fear retrieval, sends dense projections to the PVT8. Retrieval at late time points activated PL neurons projecting to the PVT, and optogenetic silencing of these projections impaired retrieval at late, but not early, time points. In contrast, silencing of PL inputs to the basolateral amygdala impaired retrieval at early, but not late, time points, indicating a time-dependent shift in retrieval circuits. Retrieval at late time points also activated PVT neurons projecting to the central nucleus of the amygdala, and silencing these projections at late, but not early, time points induced a persistent attenuation of fear. Thus, the PVT may act as a crucial thalamic node recruited into cortico-amygdalar networks for retrieval and maintenance of long-term fear memories.
来自《自然》，翻译：李伯勋，魏若妍，丁家琦，王文佳；审校：李伯勋，丁家琦
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