네이처 컨텐츠

Editorials

News

Macron consolidates electoral victory p.459

The party of France’s recently elected president won an absolute majority in its first general elections, with an agenda that included strong support for research.

Declan Butler

doi: 10.1038/549459a

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News Features

News & Views

These retinas are made for walkin' p.476

Measurements of the activity of neurons called direction-selective ganglion cells in the mouse retina explain how visual motion encoded by the eye maps onto body movements such as walking. See Article p.492

Jonathan B. Demb & Damon A. Clark

doi: 10.1038/nature22505

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No sign of asymmetry in the strong force p.477

The strong force binds the constituents of nuclei together. Differences between the force's fundamental interactions and their mirror images were thought to have been observed in heavy-ion collisions, but new data challenge this picture.

Alexandru Florin Dobrin

doi: 10.1038/nature23086

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A spoonful of sugar could be the medicine p.479

Pili are filamentous bacterial structures that promote adhesion to host cells. It emerges that a small molecule that inhibits this adhesion can prevent colonization of the mouse gut by a pathogenic bacterium. See Letter p.528

Hea-Jin Jung & Eric G. Pamer

doi: 10.1038/nature23084

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Interactions propel a magnetic dance p.481

A combination of leading-edge techniques has enabled interaction-induced magnetic motion to be observed for pairs of ultracold atoms — a breakthrough in the development of models of complex quantum behaviour. See Letter p.519

Lindsay J. LeBlanc

doi: 10.1038/546481a

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Synapses pruned in lupus p.482

Lupus is an autoimmune disease that can cause brain dysfunction. Studies in mouse models of lupus find that interferon proteins can cause the brain's immune cells to trim the synaptic connections between neurons. See Letter p.539

Sarah McGlasson & David Hunt

doi: 10.1038/nature23087

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Clouds unfazed by haze p.483

The extent to which aerosols affect climate is highly uncertain. Observations of clouds interacting with aerosols from a volcanic eruption suggest that the effect is much smaller than was once feared. See Article p.485

Bjorn Stevens

doi: 10.1038/546483a

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Articles

Strong constraints on aerosol–cloud interactions from volcanic eruptions p.485

Investigations of an Icelandic volcanic eruption confirm that sulfate aerosols caused a discernible yet transient brightening effect, as predicted, but their effect on the liquid water path was unexpectedly negligible.

Florent F. Malavelle, Jim M. Haywood, Andy Jones, Andrew Gettelman, Lieven Clarisse, Sophie Bauduin, Richard P. Allan, Inger Helene H. Karset, Jón Egill Kristjánsson, Lazaros Oreopoulos + et al.

doi: 10.1038/nature22974

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A retinal code for motion along the gravitational and body axes p.492

Global mapping shows that mouse retinal neurons prefer visual motion produced when the animal moves along two behaviourally relevant axes, allowing the encoding of the animal’s every translation and rotation.

Shai Sabbah, John A. Gemmer, Ananya Bhatia-Lin, Gabrielle Manoff, Gabriel Castro, Jesse K. Siegel, Nathan Jeffery & David M. Berson

doi: 10.1038/nature22818

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Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer p.498

Exosomes improve the delivery of siRNA to mutant KRAS in the pancreatic tumours and bypass immune clearance better than artificial liposomes, probably owing to enhanced macropinocytocis and presence of CD47 on exosomes, respectively.

Sushrut Kamerkar, Valerie S. LeBleu, Hikaru Sugimoto, Sujuan Yang, Carolina F. Ruivo, Sonia A. Melo, J. Jack Lee & Raghu Kalluri

doi: 10.1038/nature22341

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Structure of the human multidrug transporter ABCG2 p.504

The structure of human ABCG2 bound to an inhibitory antibody using cryo-electron microscopy, representing the first high-resolution structural data of a human multidrug transporter.

Nicholas M. I. Taylor, Ioannis Manolaridis, Scott M. Jackson, Julia Kowal, Henning Stahlberg & Kaspar P. Locher

doi: 10.1038/nature22345

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Letters

A massive, dead disk galaxy in the early Universe p.510

When the Universe was just 3 billion years old, half of the most massive galaxies had already ceased star formation, and such a galaxy has now been observed using gravitational lensing, unexpectedly turning out to be a compact, fast-spinning disk galaxy rather than a proto-bulge galaxy.

Sune Toft, Johannes Zabl, Johan Richard, Anna Gallazzi, Stefano Zibetti, Moire Prescott, Claudio Grillo, Allison W. S. Man, Nicholas Y. Lee, Carlos Gómez-Guijarro + et al.

doi: 10.1038/nature22388

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A giant planet undergoing extreme-ultraviolet irradiation by its hot massive-star host p.514

The giant planet KELT-9b has a dayside temperature of about 4,600 K, which is sufficiently high to dissociate molecules and to evaporate its atmosphere, owing to its hot stellar host.

B. Scott Gaudi, Keivan G. Stassun, Karen A. Collins, Thomas G. Beatty, George Zhou, David W. Latham, Allyson Bieryla, Jason D. Eastman, Robert J. Siverd, Justin R. Crepp + et al.

doi: 10.1038/nature22392

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Improved maize reference genome with single-molecule technologies OPEN p.524

An improved reference genome for maize, using single-molecule sequencing and high-resolution optical mapping, enables characterization of structural variation and repetitive regions, and identifies lineage expansions of transposable elements that are unique to maize.

Yinping Jiao, Paul Peluso, Jinghua Shi, Tiffany Liang, Michelle C. Stitzer, Bo Wang, Michael S. Campbell, Joshua C. Stein, Xuehong Wei, Chen-Shan Chin + et al.

doi: 10.1038/nature22971

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Selective depletion of uropathogenic E. coli from the gut by a FimH antagonist p.528

Both F17-like and type 1 pili promote intestinal colonization in mouse colonic crypts, and the high-affinity mannoside M4284 reduces intestinal colonization of uropathogenic Escherichia coli while simultaneously treating urinary tract infections without disrupting the composition of the gut microbiota.

Caitlin N. Spaulding, Roger D. Klein, Ségolène Ruer, Andrew L. Kau, Henry L. Schreiber, Zachary T. Cusumano, Karen W. Dodson, Jerome S. Pinkner, Daved H. Fremont, James W. Janetka + et al.

doi: 10.1038/nature22972

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Multilineage communication regulates human liver bud development from pluripotency p.533

Single-cell RNA sequencing analysis of two- and three-dimensional hepatic differentiation reveals that both systems recapitulate certain transcriptomic features of human hepatogenesis.

J. Gray Camp, Keisuke Sekine, Tobias Gerber, Henry Loeffler-Wirth, Hans Binder, Malgorzata Gac, Sabina Kanton, Jorge Kageyama, Georg Damm, Daniel Seehofer + et al.

doi: 10.1038/nature22796

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Microglia-dependent synapse loss in type I interferon-mediated lupus p.539

Abnormal behavioural phenotypes and synapse loss in the brain of lupus-prone mice are prevented by blocking type I interferon signalling, which is further shown to stimulate microglial phagocytosis of neuronal material in the brains of these mice.

Allison R. Bialas, Jessy Presumey, Abhishek Das, Cees E. van der Poel, Peter H. Lapchak, Luka Mesin, Gabriel Victora, George C. Tsokos, Christian Mawrin, Ronald Herbst + et al.

doi: 10.1038/nature22821

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Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge p.544

Histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude.

Matthew J. Emmett, Hee-Woong Lim, Jennifer Jager, Hannah J. Richter, Marine Adlanmerini, Lindsey C. Peed, Erika R. Briggs, David J. Steger, Tao Ma, Carrie A. Sims + et al.

doi: 10.1038/nature22819

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BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation p.549

BRCA1-associated protein 1 (BAP1) is a potent tumour suppressor gene that modulates environmental carcinogenesis1–3. All carriers of inherited heterozygous germline BAP1-inactivating mutations (BAP1+/-) developed one and often several BAP1-/- malignancies in their lifetime4, mostly malignant mesothelioma, uveal melanoma2,5, and so on6–10. Moreover, BAP1-acquired biallelic mutations are frequent in human cancers8,11–14. BAP1 tumour suppressor activity has been attributed to its nuclear localization, where it helps to maintain genome integrity15–17. The possible activity of BAP1 in the cytoplasm is unknown. Cells with reduced levels of BAP1 exhibit chromosomal abnormalities and decreased DNA repair by homologous recombination18, indicating that BAP1 dosage is critical. Cells with extensive DNA damage should die and not grow into malignancies. Here we discover that BAP1 localizes at the endoplasmic reticulum. Here, it binds, deubiquitylates, and stabilizes type 3 inositol-1,4,5-trisphosphate receptor (IP3R3), modulating calcium (Ca2+) release from the endoplasmic reticulum into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in BAP1+/- carriers cause reduction both of IP3R3 levels and of Ca2+ flux, preventing BAP1+/- cells that accumulate DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survive genotoxic stress, resulting in a higher rate of cellular transformation. We propose that the high incidence of cancers in BAP1+/- carriers results from the combined reduced nuclear and cytoplasmic activities of BAP1. Our data provide a mechanistic rationale for the powerful ability of BAP1 to regulate gene–environment interaction in human carcinogenesis.

Angela Bononi, Carlotta Giorgi, Simone Patergnani, David Larson, Kaitlyn Verbruggen, Mika Tanji, Laura Pellegrini, Valentina Signorato, Federica Olivetto, Sandra Pastorino + et al.

doi: 10.1038/nature22798

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PTEN counteracts FBXL2 to promote IP3R3- and Ca2+-mediated apoptosis limiting tumour growth p.554

In response to environmental cues that promote IP3 (inositol 1,4,5-trisphosphate) generation, IP3 receptors (IP3Rs) located on the endoplasmic reticulum allow the ‘quasisynaptical’ feeding of calcium to the mitochondria to promote oxidative phosphorylation. However, persistent Ca2+ release results in mitochondrial Ca2+ overload and consequent apoptosis. Among the three mammalian IP3Rs, IP3R3 appears to be the major player in Ca2+-dependent apoptosis. Here we show that the F-box protein FBXL2 (the receptor subunit of one of 69 human SCF (SKP1, CUL1, F-box protein) ubiquitin ligase complexes) binds IP3R3 and targets it for ubiquitin-, p97- and proteasome-mediated degradation to limit Ca2+ influx into mitochondria. FBXL2-knockdown cells and FBXL2-insensitive IP3R3 mutant knock-in clones display increased cytosolic Ca2+ release from the endoplasmic reticulum and sensitization to Ca2+-dependent apoptotic stimuli. The phosphatase and tensin homologue (PTEN) gene is frequently mutated or lost in human tumours and syndromes that predispose individuals to cancer. We found that PTEN competes with FBXL2 for IP3R3 binding, and the FBXL2-dependent degradation of IP3R3 is accelerated in Pten/ mouse embryonic fibroblasts and PTEN-null cancer cells. Reconstitution of PTEN-null cells with either wild-type PTEN or a catalytically dead mutant stabilizes IP3R3 and induces persistent Ca2+ mobilization and apoptosis. IP3R3 and PTEN protein levels directly correlate in human prostate cancer. Both in cell culture and xenograft models, a non-degradable IP3R3 mutant sensitizes tumour cells with low or no PTEN expression to photodynamic therapy, which is based on the ability of photosensitizer drugs to cause Ca2+-dependent cytotoxicity after irradiation with visible light. Similarly, disruption of FBXL2 localization with GGTi-2418, a geranylgeranyl transferase inhibitor, sensitizes xenotransplanted tumours to photodynamic therapy. In summary, we identify a novel molecular mechanism that limits mitochondrial Ca2+ overload to prevent cell death. Notably, we provide proof-of-principle that inhibiting IP3R3 degradation in PTEN-deregulated cancers represents a valid therapeutic strategy.

Shafi Kuchay, Carlotta Giorgi, Daniele Simoneschi, Julia Pagan, Sonia Missiroli, Anita Saraf, Laurence Florens, Michael P. Washburn, Ana Collazo-Lorduy, Mireia Castillo-Martin + et al.

doi: 10.1038/nature22965

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