Pub Date : 2006-05-30DOI: 10.6027/9789289350167-9-en
P. D. Leeuw, Sumin Kim
Riboswitches are regions of untranslated messenger RNA that switch their conformations when they bind specific metabolites to regulate the expression of proteins involved in the biosynthesis of the bound metabolites. For example, in bacteria, archaea, and eukaryotes, the production of the essential cofactor thiamine pyrophosphate (TPP) is tightly regulated by TPP-binding riboswitches. Thore et al. determined the structure of the eukaryotic Arabidopsis thaliana TPP riboswitch bound to TPP at 2.9 angstrom resolution. The structure shows how the bound "off" conformation, which suppresses expression of a gene involved in TPP biosynthesis, is stabilized. TPP riboswitches are attractive targets for antimicrobial drugs, and the structure rationalizes the mechanism of resistance to the antibiotic pyrithiamine. S. Thore, M. Leibundgut, N. Ban, Structure of the eukaryotic thiamine pyrophosphate riboswitch with its regulatory ligand. Science 312, 1208-1211 (2006). [Abstract] [Full Text]
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Enveloped viruses are wrapped in a lipid membrane; the viral envelope fuses with a host (plasma or endosomal) cell membrane, allowing penetration of the viral core into the host cell. The extracellular form of Vaccinia virus (EEV, for extracellular enveloped virus) is wrapped in two lipid envelopes, however, posing a challenge to viral entry: Fusion of the outer envelope will result in the intracellular release of a form called the intracellular mature virus (IMV), which is still surrounded by a lipid membrane. Law et al. used immunoelectron microscopy to investigate EEV invasion of PtK2 potoroo kidney cells and saw that, rather than fusing with the plasma membrane, the outer membrane became disrupted at the site of cell contact. It remained outside the cell, allowing the inner viral membrane to fuse with the plasma membrane. Outer membrane disruption occurred only at the site of cell contact and was not stimulated by binding to glass. Exposure to polyanions (PA), heparin, or dextran sulfate, however, appeared to damage the outer membrane, allowing neutralizing antibodies directed against the IMV to permeate. Outer membrane rupture depended on glycosaminoglycans on the host cell membrane, and analysis of viral mutants implicated the viral A34 and B5 proteins in the response. Intriguingly, the combination of antibodies against the IMV with intranasal administration of PA appeared to synergistically protect mice from Vaccinia-induced pneumonia, suggesting that this research not only elucidates a mechanism whereby viruses with double envelopes gain entry to cells but also may lead to new therapeutic approaches. M. Law, G. C. Carter, K. L. Roberts, M. Hollinshead, G. L. Smith, Ligand-induced and nonfusogenic dissolution of a viral membrane. Proc. Natl. Acad. Sci. U.S.A. 103, 5989-5994 (2006). [Abstract] [Full Text]
包膜病毒被包裹在脂质膜中;病毒包膜与宿主(浆体或内体)细胞膜融合，允许病毒核心渗透到宿主细胞中。然而，细胞外形式的牛痘病毒(EEV，即细胞外包膜病毒)被包裹在两个脂质包膜中，这对病毒的进入构成了挑战:外包膜的融合将导致细胞内释放一种称为细胞内成熟病毒(IMV)的形式，它仍然被脂质膜包围。Law等人使用免疫电镜研究了EEV对PtK2 potoroo肾细胞的侵袭，发现EEV并没有与质膜融合，而是在细胞接触部位破坏了外膜。它留在细胞外，让内部的病毒膜与质膜融合。外膜破坏只发生在细胞接触的部位，而不是由与玻璃的结合引起的。然而，暴露于聚阴离子(PA)、肝素或硫酸葡聚糖，似乎会破坏外膜，使针对IMV的中和抗体渗透。外膜破裂依赖于宿主细胞膜上的糖胺聚糖，对病毒突变体的分析表明，病毒A34和B5蛋白参与了反应。有趣的是，抗IMV抗体与鼻内给药PA的组合似乎可以协同保护小鼠免受牛痘诱导的肺炎，这表明该研究不仅阐明了双包膜病毒进入细胞的机制，而且可能导致新的治疗方法。M. Law, G. C. Carter, K. L. Roberts, M. Hollinshead, G. L. Smith，配体诱导和非融合性病毒膜溶解。Proc。国家的。学会科学。美国103,5989-5994(2006)。【摘要】【全文】
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Pub Date : 2005-11-08DOI: 10.1308/1741937042360373
B. Whitby
Regulation of immune responses through local catabolic depletion of tryptophan (Trp) was first identified in studies of the maternal T cell response to the fetus. This pathway, which is controlled by the enzyme indoleamine 2,3-dioxygenase (IDO), has since been identified in a variety of immunological settings. Platten et al. now find that IDO-mediated Trp catabolism also contributes during therapy of a mouse model of multiple sclerosis. By using a form of antigen termed an altered peptide ligand, T cell responses were prevented from causing inflammation and nervous system pathology, and this effect corresponded with the induction of IDO. Naturally occurring metabolites and a synthetic derivative of the IDO pathway inhibited T cell proliferation and activation of antigen-presenting cells. Remarkably, paralyzed mice recovered after being fed the synthetic derivative. M. Platten, P. P. Ho, S. Youssef, P. Fontoura, H. Garren, E. M. Hur, R. Gupta, L. Y. Lee, B. A. Kidd, W. H. Robinson, R. A. Sobel, M. L. Selley, L. Steinman, Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science 310, 850-855 (2005). [Abstract] [Full Text]
通过局部色氨酸(Trp)的分解代谢耗竭来调节免疫反应是在母体T细胞对胎儿反应的研究中首次发现的。这种途径是由吲哚胺2,3-双加氧酶(IDO)控制的，已经在各种免疫学环境中被发现。Platten等人现在发现ido介导的色氨酸分解代谢在多发性硬化症小鼠模型的治疗过程中也起作用。通过使用一种被称为改变肽配体的抗原形式，T细胞反应被阻止引起炎症和神经系统病理，这种效果与IDO的诱导相对应。天然存在的代谢物和IDO途径的合成衍生物抑制T细胞增殖和抗原呈递细胞的激活。值得注意的是，瘫痪小鼠在喂食合成衍生物后恢复了健康。M. Platten, P. P. Ho, S. Youssef, P. Fontoura, H. Garren, E. M. Hur, R. Gupta, L. Y. Lee, B. a . Kidd, W. H. Robinson, R. a . Sobel, M. L. Selley, L. Steinman，合成色氨酸代谢物治疗自身免疫性神经炎症。科学31,850-855(2005)。【摘要】【全文】
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Yeast two-hybrid analysis has been applied for detecting the interactions in the entire proteome of several model organisms. Stelzl et al. have now applied an automated yeast two-hybrid interaction mating assay to test more than 5500 human proteins (excluding those with transmembrane domains). The analysis yielded 3269 interactions, which were then scored using a confidence rating system based on six criteria, including presence of the orthologous interactions in model organism data sets, the occurrence of interactions in loops containing three or four proteins (believed to be a common property of biological interaction networks), and annotation of the interacting proteins with Gene Ontology (GO) terms for localization and cellular function. Of the 3269 interactions, 911 met three or more of the criteria and were classified as high confidence. The network was also compared with the regulatory pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG), and 66 proteins were mapped into pathways based on their position as bridges linking two or more proteins within a pathway. Two of these, ANP32A and CRMP1, were mapped into the Wnt pathway and were verified using a reporter gene assay in cells transfected to overexpress the Wnt regulator Dvl, which stimulates Wnt reporter gene expression. Both ANP32A and CRPM1 inhibited Dvl-stimulated reporter gene expression, which suggests that these proteins are novel inhibitory regulators of the Wnt pathway. Thus, in addition to allowing analysis of the network properties of a human proteome interaction network, this large-scale analysis of the human proteome also revealed novel regulators of cell signaling. U. Stelzl, U. Worm, M. Lalowski, C. Haenig, F. H. Brembeck, H. Goehler, M. Stroedicke, M. Zenkner, A. Schoenherr, S. Koeppen, J. Timm, S. Mintzlaff, C. Abraham, N. Bock, S. Kietzmann, A. Goedde, E. Toksöz, A. Droege, S. Krobitsch, B. Korn, W. Birchmeier, H. Lehrach, E. E. Wanker, A human protein-protein interaction network: A resource for annotating the proteome. Cell 122, 957-968 (2005). [PubMed]
酵母双杂交分析已被用于检测几种模式生物整个蛋白质组的相互作用。Stelzl等人现在已经应用一种自动酵母双杂交相互作用交配试验来测试5500多种人类蛋白质(不包括那些跨膜结构域的蛋白质)。该分析产生了3269种相互作用，然后使用基于六个标准的置信度评级系统对其进行评分，包括模型生物数据集中存在的同源相互作用，在包含三到四种蛋白质的环中发生的相互作用(被认为是生物相互作用网络的共同特性)，以及相互作用蛋白质与基因本体(GO)术语的注释定位和细胞功能。在3269次互动中，911次符合三个或更多的标准，被归类为高置信度。该网络还与京都基因与基因组百科全书(KEGG)中的调控途径进行了比较，并根据它们在途径中连接两个或多个蛋白质的桥梁位置将66种蛋白质映射到途径中。其中两个，ANP32A和CRMP1，被定位到Wnt通路中，并在转染过表达Wnt调节因子Dvl的细胞中使用报告基因试验进行验证，后者刺激Wnt报告基因的表达。ANP32A和CRPM1均抑制dvl刺激的报告基因表达，这表明这些蛋白是Wnt通路的新型抑制调节因子。因此，除了允许分析人类蛋白质组相互作用网络的网络特性外，这种对人类蛋白质组的大规模分析还揭示了细胞信号传导的新调节因子。U. Stelzl, U. Worm, M. Lalowski, C. Haenig, F. H. Brembeck, H. Goehler, M. Stroedicke, M. Zenkner, A. Schoenherr, S. Koeppen, J. Timm, S. Mintzlaff, C. Abraham, N. Bock, S. Kietzmann, A. Goedde, E. Toksöz, A. Droege, S. Krobitsch, B. Korn, W. Birchmeier, H. Lehrach, E. E. Wanker，蛋白质组注释资源。Cell 122, 957-968(2005)。(PubMed)
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Pub Date : 2005-02-15DOI: 10.4324/9781315172484-33
A. Psalm
Diverse human diseases such as viral infections, diabetes, and neurodegeneration are characterized at the cellular level by an inability of the endoplasmic reticulum (ER) to fold proteins properly, resulting in the onset of "ER stress." Uncorrected ER stress activates apoptotic cell death pathways, and it has been hypothesized that these pathways might be manipulated for therapeutic benefit. In a chemical screen, Boyce et al. identified a small molecule (salubrinal) that protects cells from ER-stress-induced apoptosis. Salubrinal selectively inhibited the dephosphorylation of eukaryotic translation initiation factor α (eIF2α) and inhibited herpesvirus replication. Thus, eIF2α may be a valuable drug target for diseases involving ER stress. M. Boyce, K. F. Bryant, C. Jousse, K. Long, H. P. Harding, D. Scheuner, R. J. Kaufman, D. Ma, D. M. Coen, D. Ron, J. Yuan, A selective inhibitor of eIF2α dephosphorylation protects cells from ER stress. Science 307, 935-939 (2005). [Abstract] [Full Text]
多种人类疾病，如病毒感染、糖尿病和神经退行性变，在细胞水平上的特征是内质网(ER)无法正确折叠蛋白质，导致“内质网应激”的发生。未经纠正的内质网应激激活凋亡细胞死亡途径，并且已经假设这些途径可能被操纵以获得治疗益处。在化学筛选中，Boyce等人发现了一种小分子(salubrinal)，可以保护细胞免受内质网应激诱导的凋亡。Salubrinal选择性抑制真核翻译起始因子α (eIF2α)的去磷酸化，抑制疱疹病毒的复制。因此，eIF2α可能是内质网应激相关疾病的有价值的药物靶点。M. Boyce, K. F. Bryant, C. Jousse, K. Long, H. P. Harding, D. Scheuner, R. J. Kaufman, D. Ma, D. M. Coen, D. Ron, J. Yuan。科学通报，2003,19(4)。【摘要】【全文】
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Pub Date : 2004-09-14DOI: 10.1007/978-3-540-72617-3_4
S. D. L. F. V. Bentem, T. Nühse, H. Hirt
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