Protect funding for US earthquake early-warning system p.451

doi: 10.1038/nature.2017.22162

Don’t let Europe’s open-science dream drift p.451

doi: 10.1038/546451a

Heatwaves to soar above the hot air of climate politics p.452

doi: 10.1038/546452a

Macron consolidates electoral victory p.459

doi: 10.1038/549459a

Ancient oak's youthful genome surprises biologists p.460

doi: 10.1038/546460a

China’s genomics giant to make stock-market debut p.461

doi: 10.1038/546461

Teeth tell tale of hippo’s quick spread across Africa p.462

doi: 10.1038/nature.2017.22168

New concerns raised over value of genome-wide disease studies p.463

doi: 10.1038/nature.2017.22152

China cracks down on fake peer reviews p.464

doi: 10.1038/546464a

The fight to save thousands of lives with sea-floor sensors p.466

doi: 10.1038/546466a

These retinas are made for walkin' p.476

doi: 10.1038/nature22505

No sign of asymmetry in the strong force p.477

doi: 10.1038/nature23086

A spoonful of sugar could be the medicine p.479

doi: 10.1038/nature23084

The feline line p.480

doi: 10.1038/546480a

Interactions propel a magnetic dance p.481

doi: 10.1038/546481a

Synapses pruned in lupus p.482

doi: 10.1038/nature23087

Clouds unfazed by haze p.483

doi: 10.1038/546483a

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

doi: 10.1038/nature22974

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

doi: 10.1038/nature22818

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

doi: 10.1038/nature22341

Structure of the human multidrug transporter ABCG2 p.504

doi: 10.1038/nature22345

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

doi: 10.1038/nature22388

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

doi: 10.1038/nature22392

Microscopy of the interacting Harper–Hofstadter model in the two-body limit p.519

doi: 10.1038/nature22811

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

doi: 10.1038/nature22971

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

doi: 10.1038/nature22972

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

doi: 10.1038/nature22796

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

doi: 10.1038/nature22821

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

doi: 10.1038/nature22819

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 carcinogenesis^1–3. All carriers of inherited heterozygous germline BAP1-inactivating mutations (BAP1^+/-) developed one and often several BAP1^-/- malignancies in their lifetime⁴, mostly malignant mesothelioma, uveal melanoma^2,5, and so on^6–10. Moreover, BAP1-acquired biallelic mutations are frequent in human cancers^8,11–14. BAP1 tumour suppressor activity has been attributed to its nuclear localization, where it helps to maintain genome integrity^15–17. 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.

doi: 10.1038/nature22798

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.

doi: 10.1038/nature22965

Structure of the Cpf1 endonuclease R-loop complex after target DNA cleavage p.559

doi: 10.1038/nature22398