目次

Editorial

科学者は一般の人々との関わりを深め、研究の法的・倫理的問題に関する議論に積極的に参加すべきだ。

Why researchers should resolve to engage in 2017 p.5

Debates over climate change and genome editing present the need for researchers to venture beyond their comfort zones to engage with citizens — and they should receive credit for doing so.

doi: 10.1038/541005a

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News

民間企業や研究機関が、量子コンピューターの実現に向けて本腰の競り合いを。

Quantum computers ready to leap out of the lab in 2017 p.9

Google, Microsoft and a host of labs and start-ups are racing to turn scientific curiosities into working machines.

doi: 10.1038/541009a

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かつてない規模の詳細な海洋生態系3D地図が、より良い海洋保護計画につながる可能性が。

3D ocean map tracks ecosystems in unprecedented detail p.10

Tool to divide water masses into precise categories can help in conservation planning.

doi: 10.1038/541010a

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ロイヤル島の生態学研究を継続させようと、新たなオオカミ個体を外から導入する計画が。

Wolf transplant could reset iconic island study p.12

US government proposes introducing wolves to Isle Royale as population dwindles.

doi: 10.1038/nature.2016.21217

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ライセンス交渉の不調により、ドイツ、台湾、ペルーの科学者がエルゼビア社の雑誌にアクセスできない状況に。

Scientists in Germany, Peru and Taiwan to lose access to Elsevier journals p.13

Libraries pursue alternative delivery routes after licence negotiations break down.

doi: 10.1038/nature.2016.21223

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Natureが予想する、2017年の科学を彩るものは?

2017 sneak peek: What the new year holds for science p.14

Expect researchers to glimpse an event horizon, continue striving for quantum supremacy and brace themselves for a political hangover.

doi: 10.1038/541014a

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News Features

生態学:海辺の鳥に死をもたらすのは?

What’s killing the world’s shorebirds? p.16

doi: 10.1038/541016a

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News & Views

天文学:「犯行現場」が突き止められた電波バースト

Astronomy: Radio burst caught red-handed p.32

10年ほど前から、遠方宇宙からの強い電波バーストが複数観測されているが、その起源は不明だった。そのようなバーストの1つの起源が今回突き止められたが、この知見は謎をさらに深めるばかりである。

doi: 10.1038/541032a

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構造生物学:イオンチャネル作用機構の解明

Structural biology: Ion-channel mechanisms revealed p.33

カリウムイオンを細胞外に放出するSlo1チャネルの構造から、その高いコンダクタンスとカルシウムイオンと膜電位上昇による二重活性化機構との基盤に関する手掛かりが得られた。

doi: 10.1038/nature21103

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DNA修復:神経変性疾患で働く機構の一本化

DNA repair: A unifying mechanism in neurodegeneration p.34

これまで性質が調べられていなかった遺伝性疾患の発症機構の研究から、DNA修復機構の異常が一部の神経変性疾患に共通していることが明確になり、このような疾患の治療法候補が示唆された。

doi: 10.1038/nature21107

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植物科学:太陽光を効率よく使うタバコ

Plant science: Crops on the fast track for light p.36

タバコに遺伝学的操作を加えて光強度の変化への適応を改善することが試みられ、操作を受けた植物は野生型の植物よりも太陽光をもっと安全かつ効率よく使用できることが示された。

doi: 10.1038/541036a

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化学:触媒作用への長くて曲がりくねった道

Chemistry: The long and winding road to catalysis p.37

ある部位で水素分子から作り出された水素原子が、そこからこぼれ出て別の部位で他の原子あるいは分子に付加される過程を、化学触媒分野ではスピルオーバーと呼んでいる。新たな研究によって、この作用の詳細が明らかになった。

doi: 10.1038/541037a

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システム生物学:細胞ファミリーが持つ分子記憶

Systems biology: Molecular memoirs of a cellular family p.38

細胞内DNAに埋め込まれたバーコード配列にランダムな修飾を導入するシステムを使えば、細胞間の系統的関係を見分けることができ、同時に細胞の空間的関係は保持できることが分かった。

doi: 10.1038/nature21101

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Articles

がん:転移開始細胞の脂肪酸受容体CD36を介した標的化

Targeting metastasis-initiating cells through the fatty acid receptor CD36 p.41

Human oral carcinoma cells expressing high levels of the fatty acid receptor CD36 initiate metastasis in mouse models, and metastasis is increased by palmitic acid or a fatty diet and decreased by blockade of CD36.

doi: 10.1038/nature20791

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構造生物学:開状態にある高コンダクタンスCa2+活性化K+チャネルの低温電子顕微鏡構造

Cryo-EM structure of the open high-conductance Ca2+-activated K+ channel p.46

Two complementary studies present the full-length high-resolution structure of a Slo1 channel in the presence or absence of Ca2+ sensor in addition to the voltage sensor’s direct action on the pore.

doi: 10.1038/nature20608

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構造生物学:高コンダクタンスCa2+活性化K+チャネルでのゲート開閉の構造的基盤

Structural basis for gating the high-conductance Ca2+-activated K+ channel p.52

Two complementary studies present the full-length high-resolution structure of a Slo1 channel in the presence or absence of Ca2+ ions, in which an unconventional allosteric voltage-sensing mechanism regulates the Ca2+ sensor in addition to the voltage sensor’s direct action on the pore.

doi: 10.1038/nature20775

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Letters

天文学:高速電波バーストとそのホスト天体の直接的な位置決定

A direct localization of a fast radio burst and its host p.58

Fast radio bursts are astronomical radio flashes of unknown physical nature with durations of milliseconds. Their dispersive arrival times suggest an extragalactic origin and imply radio luminosities that are orders of magnitude larger than those of all known short-duration radio transients. So far all fast radio bursts have been detected with large single-dish telescopes with arcminute localizations, and attempts to identify their counterparts (source or host galaxy) have relied on the contemporaneous variability of field sources or the presence of peculiar field stars or galaxies. These attempts have not resulted in an unambiguous association with a host or multi-wavelength counterpart. Here we report the subarcsecond localization of the fast radio burst FRB 121102, the only known repeating burst source, using high-time-resolution radio interferometric observations that directly image the bursts. Our precise localization reveals that FRB 121102 originates within 100 milliarcseconds of a faint 180-microJansky persistent radio source with a continuum spectrum that is consistent with non-thermal emission, and a faint (twenty-fifth magnitude) optical counterpart. The flux density of the persistent radio source varies by around ten per cent on day timescales, and very long baseline radio interferometry yields an angular size of less than 1.7 milliarcseconds. Our observations are inconsistent with the fast radio burst having a Galactic origin or its source being located within a prominent star-forming galaxy. Instead, the source appears to be co-located with a low-luminosity active galactic nucleus or a previously unknown type of extragalactic source. Localization and identification of a host or counterpart has been essential to understanding the origins and physics of other kinds of transient events, including gamma-ray bursts and tidal disruption events. However, if other fast radio bursts have similarly faint radio and optical counterparts, our findings imply that direct subarcsecond localizations may be the only way to provide reliable associations.

doi: 10.1038/nature20797

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光物理学:二次元半導体ヘテロ構造体における相関した蛍光の点滅

Correlated fluorescence blinking in two-dimensional semiconductor heterostructures p.62

‘Blinking’, or ‘fluorescence intermittency’, refers to a random switching between ‘ON’ (bright) and ‘OFF’ (dark) states of an emitter; it has been studied widely in zero-dimensional quantum dots and molecules, and scarcely in one-dimensional systems. A generally accepted mechanism for blinking in quantum dots involves random switching between neutral and charged states (or is accompanied by fluctuations in charge-carrier traps), which substantially alters the dynamics of radiative and non-radiative decay. Here, we uncover a new type of blinking effect in vertically stacked, two-dimensional semiconductor heterostructures, which consist of two distinct monolayers of transition metal dichalcogenides (TMDs) that are weakly coupled by van der Waals forces. Unlike zero-dimensional or one-dimensional systems, two-dimensional TMD heterostructures show a correlated blinking effect, comprising randomly switching bright, neutral and dark states. Fluorescence cross-correlation spectroscopy analyses show that a bright state occurring in one monolayer will simultaneously lead to a dark state in the other monolayer, owing to an intermittent interlayer carrier-transfer process. Our findings suggest that bilayer van der Waals heterostructures provide unique platforms for the study of charge-transfer dynamics and non-equilibrium-state physics, and could see application as correlated light emitters in quantum technology.

doi: 10.1038/nature20601

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化学:触媒担体が水素スピルオーバーに及ぼす影響

Catalyst support effects on hydrogen spillover p.68

Hydrogen spillover is the surface migration of activated hydrogen atoms from a metal catalyst particle, on which they are generated, onto the catalyst support. The phenomenon has been much studied and its occurrence on reducible supports such as titanium oxide is established, yet questions remain about whether hydrogen spillover can take place on nonreducible supports such as aluminium oxide. Here we use the enhanced precision of top-down nanofabrication to prepare controlled and precisely tunable model systems that allow us to quantify the efficiency and spatial extent of hydrogen spillover on both reducible and nonreducible supports. We place multiple pairs of iron oxide and platinum nanoparticles on titanium oxide and aluminium oxide supports, varying the distance between the pairs from zero to 45 nanometres with a precision of one nanometre. We then observe the extent of the reduction of the iron oxide particles by hydrogen atoms generated on the platinum using single-particle in situ X-ray absorption spectromicroscopy applied simultaneously to all particle pairs. The data, in conjunction with density functional theory calculations, reveal fast hydrogen spillover on titanium oxide that reduces remote iron oxide nanoparticles via coupled proton–electron transfer. In contrast, spillover on aluminium oxide is mediated by three-coordinated aluminium centres that also interact with water and that give rise to hydrogen mobility competing with hydrogen desorption; this results in hydrogen spillover about ten orders of magnitude slower than on titanium oxide and restricted to very short distances from the platinum particle. We anticipate that these observations will improve our understanding of hydrogen storage and catalytic reactions involving hydrogen, and that our approach to creating and probing model catalyst systems will provide opportunities for studying the origin of synergistic effects in supported catalysts that combine multiple functionalities.

doi: 10.1038/nature20782

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気候科学:南極氷床の流出によって増幅される百年スケールの完新世気候変動

Centennial-scale Holocene climate variations amplified by Antarctic Ice Sheet discharge p.72

Proxy-based indicators of past climate change show that current global climate models systematically underestimate Holocene-epoch climate variability on centennial to multi-millennial timescales, with the mismatch increasing for longer periods. Proposed explanations for the discrepancy include ocean–atmosphere coupling that is too weak in models, insufficient energy cascades from smaller to larger spatial and temporal scales, or that global climate models do not consider slow climate feedbacks related to the carbon cycle or interactions between ice sheets and climate. Such interactions, however, are known to have strongly affected centennial- to orbital-scale climate variability during past glaciations, and are likely to be important in future climate change. Here we show that fluctuations in Antarctic Ice Sheet discharge caused by relatively small changes in subsurface ocean temperature can amplify multi-centennial climate variability regionally and globally, suggesting that a dynamic Antarctic Ice Sheet may have driven climate fluctuations during the Holocene. We analysed high-temporal-resolution records of iceberg-rafted debris derived from the Antarctic Ice Sheet, and performed both high-spatial-resolution ice-sheet modelling of the Antarctic Ice Sheet and multi-millennial global climate model simulations. Ice-sheet responses to decadal-scale ocean forcing appear to be less important, possibly indicating that the future response of the Antarctic Ice Sheet will be governed more by long-term anthropogenic warming combined with multi-centennial natural variability than by annual or decadal climate oscillations.

doi: 10.1038/nature20582

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気候科学:棚氷下の堆積物が記録した20世紀におけるパイン島氷河後退の歴史

Sub-ice-shelf sediments record history of twentieth-century retreat of Pine Island Glacier p.77

The West Antarctic Ice Sheet is one of the largest potential sources of rising sea levels. Over the past 40 years, glaciers flowing into the Amundsen Sea sector of the ice sheet have thinned at an accelerating rate, and several numerical models suggest that unstable and irreversible retreat of the grounding line—which marks the boundary between grounded ice and floating ice shelf—is underway. Understanding this recent retreat requires a detailed knowledge of grounding-line history, but the locations of the grounding line before the advent of satellite monitoring in the 1990s are poorly dated. In particular, a history of grounding-line retreat is required to understand the relative roles of contemporaneous ocean-forced change and of ongoing glacier response to an earlier perturbation in driving ice-sheet loss. Here we show that the present thinning and retreat of Pine Island Glacier in West Antarctica is part of a climatically forced trend that was triggered in the 1940s. Our conclusions arise from analysis of sediment cores recovered beneath the floating Pine Island Glacier ice shelf, and constrain the date at which the grounding line retreated from a prominent seafloor ridge. We find that incursion of marine water beyond the crest of this ridge, forming an ocean cavity beneath the ice shelf, occurred in 1945 (±12 years); final ungrounding of the ice shelf from the ridge occurred in 1970 (±4 years). The initial opening of this ocean cavity followed a period of strong warming of West Antarctica, associated with El Niño activity. Thus our results suggest that, even when climate forcing weakened, ice-sheet retreat continued.

doi: 10.1038/nature20136

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肥満:ボディーマス指数のエピゲノム規模の関連研究と肥満の有害転帰

Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity p.81

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10−7, range P = 9.2 × 10−8 to 6.0 × 10−46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10−6, range P = 5.5 × 10−6 to 6.1 × 10−35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07–2.56); P = 1.1 × 10−54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.

doi: 10.1038/nature20784

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神経変性:XRCC1変異はPARP1の過剰な活性化および小脳性運動失調症に関連する

XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia p.87

XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease.

doi: 10.1038/nature20790

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植物科学:節での輸送体欠損によりイネの穀粒中のリン蓄積量を減少させる

Reducing phosphorus accumulation in rice grains with an impaired transporter in the node p.92

Phosphorus is an important nutrient for crop productivity. More than 60% of the total phosphorus in cereal crops is finally allocated into the grains and is therefore removed at harvest. This removal accounts for 85% of the phosphorus fertilizers applied to the field each year. However, because humans and non-ruminants such as poultry, swine and fish cannot digest phytate, the major form of phosphorus in the grains, the excreted phosphorus causes eutrophication of waterways. A reduction in phosphorus accumulation in the grain would contribute to sustainable and environmentally friendly agriculture. Here we describe a rice transporter, SULTR-like phosphorus distribution transporter (SPDT), that controls the allocation of phosphorus to the grain. SPDT is expressed in the xylem region of both enlarged- and diffuse-vascular bundles of the nodes, and encodes a plasma-membrane-localized transporter for phosphorus. Knockout of this gene in rice (Oryza sativa) altered the distribution of phosphorus, with decreased phosphorus in the grains but increased levels in the leaves. Total phosphorus and phytate in the brown de-husked rice were 20–30% lower in the knockout lines, whereas yield, seed germination and seedling vigour were not affected. These results indicate that SPDT functions in the rice node as a switch to allocate phosphorus preferentially to the grains. This finding provides a potential strategy to reduce the removal of phosphorus from the field and lower the risk of eutrophication of waterways.

doi: 10.1038/nature20610

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免疫学:線維症に関与する非典型的単球と、その運命拘束された前駆細胞の発見

Identification of an atypical monocyte and committed progenitor involved in fibrosis p.96

Monocytes and macrophages comprise a variety of subsets with diverse functions. It is thought that these cells play a crucial role in homeostasis of peripheral organs, key immunological processes and development of various diseases. Among these diseases, fibrosis is a life-threatening disease of unknown aetiology. Its pathogenesis is poorly understood, and there are few effective therapies. The development of fibrosis is associated with activation of monocytes and macrophages. However, the specific subtypes of monocytes and macrophages that are involved in fibrosis have not yet been identified. Here we show that Ceacam1+Msr1+Ly6CF4/80Mac1+ monocytes, which we term segregated-nucleus-containing atypical monocytes (SatM), share granulocyte characteristics, are regulated by CCAAT/enhancer binding protein β (C/EBPβ), and are critical for fibrosis. Cebpb deficiency results in a complete lack of SatM. Furthermore, the development of bleomycin-induced fibrosis, but not inflammation, was prevented in chimaeric mice with Cebpb−/− haematopoietic cells. Adoptive transfer of SatM into Cebpb−/− mice resulted in fibrosis. Notably, SatM are derived from Ly6CFcεRI+ granulocyte/macrophage progenitors, and a newly identified SatM progenitor downstream of Ly6CFcεRI+ granulocyte/macrophage progenitors, but not from macrophage/dendritic-cell progenitors. Our results show that SatM are critical for fibrosis and that C/EBPβ licenses differentiation of SatM from their committed progenitor.

doi: 10.1038/nature20611

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老化:スプライシング因子1は線虫の食餌制限およびTORC1経路による寿命を調節する

Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans p.102

Ageing is driven by a loss of transcriptional and protein homeostasis and is the key risk factor for multiple chronic diseases. Interventions that attenuate or reverse systemic dysfunction associated with age therefore have the potential to reduce overall disease risk in the elderly. Precursor mRNA (pre-mRNA) splicing is a fundamental link between gene expression and the proteome, and deregulation of the splicing machinery is linked to several age-related chronic illnesses. However, the role of splicing homeostasis in healthy ageing remains unclear. Here we demonstrate that pre-mRNA splicing homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans. Using transcriptomics and in-depth splicing analysis in young and old animals fed ad libitum or subjected to dietary restriction, we find defects in global pre-mRNA splicing with age that are reduced by dietary restriction via splicing factor 1 (SFA-1; the C. elegans homologue of SF1, also known as branchpoint binding protein, BBP). We show that SFA-1 is specifically required for lifespan extension by dietary restriction and by modulation of the TORC1 pathway components AMPK, RAGA-1 and RSKS-1/S6 kinase. We also demonstrate that overexpression of SFA-1 is sufficient to extend lifespan. Together, these data demonstrate a role for RNA splicing homeostasis in dietary restriction longevity and suggest that modulation of specific spliceosome components may prolong healthy ageing.

doi: 10.1038/nature20789

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発生生物学:単一細胞における系譜情報の合成記録とin situ読み出し

Synthetic recording and in situ readout of lineage information in single cells p.107

Reconstructing the lineage relationships and dynamic event histories of individual cells within their native spatial context is a long-standing challenge in biology. Many biological processes of interest occur in optically opaque or physically inaccessible contexts, necessitating approaches other than direct imaging. Here we describe a synthetic system that enables cells to record lineage information and event histories in the genome in a format that can be subsequently read out of single cells in situ. This system, termed memory by engineered mutagenesis with optical in situ readout (MEMOIR), is based on a set of barcoded recording elements termed scratchpads. The state of a given scratchpad can be irreversibly altered by CRISPR/Cas9-based targeted mutagenesis, and later read out in single cells through multiplexed single-molecule RNA fluorescence hybridization (smFISH). Using MEMOIR as a proof of principle, we engineered mouse embryonic stem cells to contain multiple scratchpads and other recording components. In these cells, scratchpads were altered in a progressive and stochastic fashion as the cells proliferated. Analysis of the final states of scratchpads in single cells in situ enabled reconstruction of lineage information from cell colonies. Combining analysis of endogenous gene expression with lineage reconstruction in the same cells further allowed inference of the dynamic rates at which embryonic stem cells switch between two gene expression states. Finally, using simulations, we show how parallel MEMOIR systems operating in the same cell could enable recording and readout of dynamic cellular event histories. MEMOIR thus provides a versatile platform for information recording and in situ, single-cell readout across diverse biological systems.

doi: 10.1038/nature20777

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構造生物学:一本鎖RNAウイルスのゲノムとゲノム送達装置のin situ構造

In situ structures of the genome and genome-delivery apparatus in a single-stranded RNA virus p.112

Packaging of the genome into a protein capsid and its subsequent delivery into a host cell are two fundamental processes in the life cycle of a virus. Unlike double-stranded DNA viruses, which pump their genome into a preformed capsid, single-stranded RNA (ssRNA) viruses, such as bacteriophage MS2, co-assemble their capsid with the genome; however, the structural basis of this co-assembly is poorly understood. MS2 infects Escherichia coli via the host ‘sex pilus’ (F-pilus); it was the first fully sequenced organism and is a model system for studies of translational gene regulation, RNA–protein interactions, and RNA virus assembly. Its positive-sense ssRNA genome of 3,569 bases is enclosed in a capsid with one maturation protein monomer and 89 coat protein dimers arranged in a T = 3 icosahedral lattice. The maturation protein is responsible for attaching the virus to an F-pilus and delivering the viral genome into the host during infection, but how the genome is organized and delivered is not known. Here we describe the MS2 structure at 3.6 Å resolution, determined by electron-counting cryo-electron microscopy (cryoEM) and asymmetric reconstruction. We traced approximately 80% of the backbone of the viral genome, built atomic models for 16 RNA stem–loops, and identified three conserved motifs of RNA–coat protein interactions among 15 of these stem–loops with diverse sequences. The stem–loop at the 3′ end of the genome interacts extensively with the maturation protein, which, with just a six-helix bundle and a six-stranded β-sheet, forms a genome-delivery apparatus and joins 89 coat protein dimers to form a capsid. This atomic description of genome–capsid interactions in a spherical ssRNA virus provides insight into genome delivery via the host sex pilus and mechanisms underlying ssRNA–capsid co-assembly, and inspires speculation about the links between nucleoprotein complexes and the origins of viruses.

doi: 10.1038/nature20589

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ウイルス学:インフルエンザポリメラーゼとPol II CTD間の必須な相互作用の構造基盤

Structural basis of an essential interaction between influenza polymerase and Pol II CTD p.117

The heterotrimeric influenza polymerase (FluPol), comprising subunits PA, PB1 and PB2, binds to the conserved 5′ and 3′ termini (the ‘promoter’) of each of the eight single-stranded viral RNA (vRNA) genome segments and performs both transcription and replication of vRNA in the infected cell nucleus. To transcribe viral mRNAs, FluPol associates with cellular RNA polymerase II (Pol II), which enables it to take 5′-capped primers from nascent Pol II transcripts. Here we present a co-crystal structure of bat influenza A polymerase bound to a Pol II C-terminal domain (CTD) peptide mimic, which shows two distinct phosphoserine-5 (SeP5)-binding sites in the polymerase PA subunit, accommodating four CTD heptad repeats overall. Mutagenesis of the SeP5-contacting basic residues (PA K289, R454, K635 and R638) weakens CTD repeat binding in vitro without affecting the intrinsic cap-primed (transcription) or unprimed (replication) RNA synthesis activity of recombinant polymerase, whereas in cell-based minigenome assays the same mutations substantially reduce overall polymerase activity. Only recombinant viruses with a single mutation in one of the SeP5-binding sites can be rescued, but these viruses are severely attenuated and genetically unstable. Several previously described mutants that modulate virulence can be rationalized by our results, including a second site mutation (PA(C453R)) that enables the highly attenuated mutant virus (PA(R638A)) to revert to near wild-type infectivity. We conclude that direct binding of FluPol to the SeP5 Pol II CTD is fine-tuned to allow efficient viral transcription and propose that the CTD-binding site on FluPol could be targeted for antiviral drug development.

doi: 10.1038/nature20594

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