Volume 531 Issue 7596

Editorials

Time out p.549

Artificial fixes to make the most of summer time may do more harm than good.

doi: 10.1038/531549b

Play nicely p.549

Attempts by digital companies to curb unpleasant behaviour online could make the Internet a more welcoming and useful space.

doi: 10.1038/531549a

Honey trap p.550

Psychology drives some overindulgence — and it could help us to resist.

doi: 10.1038/531550a

News

News Features

News & Views

Calcium contradictions in cilia p.582

Organelles called primary cilia that protrude from cells have been thought to sense the surrounding environment through calcium-channel proteins that respond to force. Two scientists discuss the implications for developmental biology and kidney disease of a study that challenges this hypothesis. See Letter p.656

doi: 10.1038/nature17313

Killers on sterols p.583

Increasing cholesterol levels in the cell membranes of killer T cells boosts the cells' ability to mount an immune response against tumour cells in mice. Such a strategy might be valuable in anticancer immunotherapies. See Letter p.651

doi: 10.1038/nature17310

Gravity measurements on chips p.585

Gravimeters have applications ranging from oil exploration to the detection of underground tunnels, but size and lack of portability have limited their field use. A device the size of a postage stamp promises fresh opportunities. See Letter p.614

doi: 10.1038/531585a

Ironing out smoking-related airway disease p.586

Lack of the protein IRP2 in mice prevents organelles called mitochondria from accumulating toxic levels of iron in response to smoke exposure. This discovery links environmental and genetic risk factors for a chronic lung disease.

doi: 10.1038/nature17309

A close-up view of coupled molecules p.587

Processes such as photosynthesis depend on the interplay between the electric dipoles of chromophore molecules. Yet these dipole–dipole interactions have not been visualized at the atomic level — until now. See Letter p.623

doi: 10.1038/531587a

Making risk-takers settle p.588

In rats, individual differences in risk preference and in sensitivity to gains compared with losses are controlled by a specific neuronal population, stimulation of which neutralizes risk-seeking behaviour. See Letter p.642

doi: 10.1038/nature17314

Articles

Cullin–RING ubiquitin E3 ligase regulation by the COP9 signalosome p.598

Much of the intracellular protein degradation in eukaryotes is controlled by cullin–RING ubiquitin ligases (CRLs), a vast class of enzymes which are regulated by the COP9 signalosome (CSN); structural characterization of CSN–N8CRL4A complexes by cryo-electron microscopy reveals an induced-fit mechanism of CSN activation triggered only by catalytically activated CRLs without bound substrate, explaining how CSN acts as a global regulator of CRLs.

doi: 10.1038/nature17416

Letters

R-process enrichment from a single event in an ancient dwarf galaxy p.610

It has long been debated whether elements heavier than zinc are formed continually, for example in core-collapse supernovae, or in rare events, such as neutron star mergers; here, studies of element abundances in a local ultrafaint dwarf galaxy provide evidence that these elements are formed during rare yet prolific stellar events.

doi: 10.1038/nature17425

Measurement of the Earth tides with a MEMS gravimeter p.614

A light-weight, low-cost microelectromechanical system gravimeter is presented with sensitivity and stability high enough to measure the elastic deformation of the Earth’s crust as a result of tidal forces, enabling many applications.

doi: 10.1038/nature17397

Soft surfaces of nanomaterials enable strong phonon interactions p.618

A combined experimental and theoretical investigation of phononic properties in nanocrystal-based semiconductors reveals that unusually strong coupling between phonons and electrons originates from the mechanical softness of the surfaces of the nanocrystalline domains and sheds new light on charge carrier recombination in nanocrystal-based devices.

doi: 10.1038/nature16977

Visualizing coherent intermolecular dipole–dipole coupling in real space p.623

Luminescence induced by highly localized excitations that are produced by electrons tunnelling from the tip of a scanning tunnelling microscope is used to map the spatial distribution of the excitonic coupling in well-defined arrangements of a few zinc-phthalocyanine molecules and the dependence of this spatial distribution on the relative orientation and phase of the transition dipoles of the individual molecules.

doi: 10.1038/nature17428

Boreal and temperate trees show strong acclimation of respiration to warming p.633

Acclimation of leaf respiration to a 3–5-year period of warming by 3.4 °C for 10 North American tree species in forest conditions eliminated 80% of the increase in leaf respiration expected of non-acclimated trees; this suggests that the increase in respiration rates of terrestrial plants from climate warming, and the associated increase in atmospheric CO2 levels, may be less than anticipated.

doi: 10.1038/nature17142

The mid-developmental transition and the evolution of animal body plans p.637

Embryos in a particular phylum of the animal kingdom tend to most resemble one another at a stage in the middle of embryogenesis known as the phylotypic period; a transcriptional analysis of embryogenesis from single embryos of ten different phyla reveals that the transcripts expressed at the phylotypic stage (or mid-developmental transition) differ greatly between phyla, and a ‘phylum’ may be defined as a set of species sharing the same signals and transcription factor networks during the mid-developmental transition.

doi: 10.1038/nature16994

Nucleus accumbens D2R cells signal prior outcomes and control risky decision-making p.642

Increased activity of dopamine receptor type-2 (D2R)-expressing cells in the nucleus accumbens of rats during a ‘decision’ period reflects a ‘loss’ outcome of the previous decision and predicts a subsequent safe choice; by artificially increasing the activity of D2R neurons during the decision period, risk-seeking rats could be converted to risk-avoiding rats.

doi: 10.1038/nature17400

Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism p.651

CD8+ T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8+ T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8+ T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8+ but not CD4+ T cells. This is due to the increase in the plasma membrane cholesterol level of CD8+ T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8+ T cells were better than wild-type CD8+ T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.

doi: 10.1038/nature17412

β-Arrestin biosensors reveal a rapid, receptor-dependent activation/deactivation cycle p.661

(β-)Arrestins are important regulators of G-protein-coupled receptors (GPCRs). They bind to active, phosphorylated GPCRs and thereby shut off ‘classical’ signalling to G proteins, trigger internalization of GPCRs via interaction with the clathrin machinery and mediate signalling via ‘non-classical’ pathways. In addition to two visual arrestins that bind to rod and cone photoreceptors (termed arrestin1 and arrestin4), there are only two (non-visual) β-arrestin proteins (β-arrestin1 and β-arrestin2, also termed arrestin2 and arrestin3), which regulate hundreds of different (non-visual) GPCRs. Binding of these proteins to GPCRs usually requires the active form of the receptors plus their phosphorylation by G-protein-coupled receptor kinases (GRKs). The binding of receptors or their carboxy terminus as well as certain truncations induce active conformations of (β-)arrestins that have recently been solved by X-ray crystallography. Here we investigate both the interaction of β-arrestin with GPCRs, and the β-arrestin conformational changes in real time and in living human cells, using a series of fluorescence resonance energy transfer (FRET)-based β-arrestin2 biosensors. We observe receptor-specific patterns of conformational changes in β-arrestin2 that occur rapidly after the receptor–β-arrestin2 interaction. After agonist removal, these changes persist for longer than the direct receptor interaction. Our data indicate a rapid, receptor-type-specific, two-step binding and activation process between GPCRs and β-arrestins. They further indicate that β-arrestins remain active after dissociation from receptors, allowing them to remain at the cell surface and presumably signal independently. Thus, GPCRs trigger a rapid, receptor-specific activation/deactivation cycle of β-arrestins, which permits their active signalling.

doi: 10.1038/nature17198

The conformational signature of β-arrestin2 predicts its trafficking and signalling functions p.665

Arrestins are cytosolic proteins that regulate G-protein-coupled receptor (GPCR) desensitization, internalization, trafficking and signalling. Arrestin recruitment uncouples GPCRs from heterotrimeric G proteins, and targets the proteins for internalization via clathrin-coated pits. Arrestins also function as ligand-regulated scaffolds that recruit multiple non-G-protein effectors into GPCR-based ‘signalsomes’. Although the dominant function(s) of arrestins vary between receptors, the mechanism whereby different GPCRs specify these divergent functions is unclear. Using a panel of intramolecular fluorescein arsenical hairpin (FlAsH) bioluminescence resonance energy transfer (BRET) reporters to monitor conformational changes in β-arrestin2, here we show that GPCRs impose distinctive arrestin ‘conformational signatures’ that reflect the stability of the receptor–arrestin complex and role of β-arrestin2 in activating or dampening downstream signalling events. The predictive value of these signatures extends to structurally distinct ligands activating the same GPCR, such that the innate properties of the ligand are reflected as changes in β-arrestin2 conformation. Our findings demonstrate that information about ligand–receptor conformation is encoded within the population average β-arrestin2 conformation, and provide insight into how different GPCRs can use a common effector for different purposes. This approach may have application in the characterization and development of functionally selective GPCR ligands and in identifying factors that dictate arrestin conformation and function.

doi: 10.1038/nature17154