Volume 546 Number 7659

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.

doi: 10.1038/549459a

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

doi: 10.1038/nature22505

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.

doi: 10.1038/nature23086

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

doi: 10.1038/nature23084

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

doi: 10.1038/546481a

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

doi: 10.1038/nature23087

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

doi: 10.1038/546483a

Articles

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.

doi: 10.1038/nature22388

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.

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