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Nucleic acids from bacteria or viruses induce potent immune responses in infected cells1-4. The detection of pathogen-derived nucleic acids is a central strategy by which the host senses infection and initiates protective immune responses5,6. Cyclic GMP-AMP synthase (cGAS) is a double-stranded DNA sensor7,8. It catalyses the synthesis of cyclic GMP-AMP (cGAMP)9-12, which stimulates the induction of type I interferons through the STING-TBK1-IRF-3 signalling axis13-15. STING oligomerizes after binding of cGAMP, leading to the recruitment and activation of the TBK1 kinase8,16. The IRF-3 transcription factor is then recruited to the signalling complex and activated by TBK18,17-20. Phosphorylated IRF-3 translocates to the nucleus and initiates the expression of type I interferons21. However, the precise mechanisms that govern activation of STING by cGAMP and subsequent activation of TBK1 by STING remain unclear. Here we show that a conserved PLPLRT/SD motif within the C-terminal tail of STING mediates the recruitment and activation of TBK1. Crystal structures of TBK1 bound to STING reveal that the PLPLRT/SD motif binds to the dimer interface of TBK1. Cell-based studies confirm that the direct interaction between TBK1 and STING is essential for induction of IFNβ after cGAMP stimulation. Moreover, we show that full-length STING oligomerizes after it binds cGAMP, and highlight this as an essential step in the activation of STING-mediated signalling. These findings provide a structural basis for the development of STING agonists and antagonists for the treatment of cancer and autoimmune disorders.

Ubiquitin-mediated targeting of intracellular bacteria to the autophagy pathway is a key innate defence mechanism against invading microbes, including the important human pathogen Mycobacterium tuberculosis. However, the ubiquitin ligases responsible for catalysing ubiquitin chains that surround intracellular bacteria are poorly understood. The parkin protein is a ubiquitin ligase with a well-established role in mitophagy, and mutations in the parkin gene (PARK2) lead to increased susceptibility to Parkinson's disease. Surprisingly, genetic polymorphisms in the PARK2 regulatory region are also associated with increased susceptibility to intracellular bacterial pathogens in humans, including Mycobacterium leprae and Salmonella enterica serovar Typhi, but the function of parkin in immunity has remained unexplored. Here we show that parkin has a role in ubiquitin-mediated autophagy of M. tuberculosis. Both parkin-deficient mice and flies are sensitive to various intracellular bacterial infections, indicating parkin has a conserved role in metazoan innate defence. Moreover, our work reveals an unexpected functional link between mitophagy and infectious disease.

The stimulation of glucose uptake by insulin in muscle and adipose tissue requires translocation of the GLUT4 glucose transporter protein from intracellular storage sites to the cell surface. Although the cellular dynamics of GLUT4 vesicle trafficking are well described, the signalling pathways that link the insulin receptor to GLUT4 translocation remain poorly understood. Activation of phosphatidylinositol-3-OH kinase (PI(3)K) is required for this trafficking event, but it is not sufficient to produce GLUT4 translocation. We previously described a pathway involving the insulin-stimulated tyrosine phosphorylation of Cbl, which is recruited to the insulin receptor by the adapter protein CAP. On phosphorylation, Cbl is translocated to lipid rafts. Blocking this step completely inhibits the stimulation of GLUT4 translocation by insulin. Here we show that phosphorylated Cbl recruits the CrkII-C3G complex to lipid rafts, where C3G specifically activates the small GTP-binding protein TC10. This process is independent of PI(3)K, but requires the translocation of Cbl, Crk and C3G to the lipid raft. The activation of TC10 is essential for insulin-stimulated glucose uptake and GLUT4 translocation. The TC10 pathway functions in parallel with PI(3)K to stimulate fully GLUT4 translocation in response to insulin.

Temperature fluctuations in the cosmic microwave background are a key prediction of cosmological models of structure formation in the early Universe. Ground-based multi-frequency radio observations of the microwave background reveal well defined features that are not of atmospheric or Galactic origin; instead, they delineate the primordial density perturbations from which the structure in the present Universe originated. The amplitude of these perturbations confirms the earlier statistical detection by the COBE satellite.

Galaxy formation by gravitational instability implies the presence of temperature fluctuations in the cosmic microwave background. New observations at 10.45 and 14.9 GHz from the Observatorio del Teide in Tenerife on angular scales of several degrees reveal structure of galactic origin at the lower frequency, while at the upper frequency the magnitude of fluctuations of cosmological origin must be less than 1.8 x 10−5 on a scale of 5°. This strongly constrains models of galaxy formation, and is compatible with the recently announced discovery by the COBE satellite of fluctuations on larger angular scales.

The rise in atmospheric chlorine levels caused by the emission of chlorofluorocarbons and other halocarbons is thought to be the main cause of the appearance of the Antarctic ozone 'hole' in the late 1970s, and the more modest ozone depletion observed over parts of the Northern Hemisphere. Atmospheric bromine, also associated with halocarbon emissions, is believed to contribute to ozone depletion. Over the next decade, further increases in these compounds are inevitable. Model calculations show that by the end of the next century, atmospheric chlorine and bromine levels may return to those prevalent before the onset of the ozone hole, but only if more stringent regulations are applied to halocarbon production than those currently proposed. © 1990 Nature Publishing Group.

For policymakers, biodiversity can present more complex challenges than climate change, argue Michel Loreau, Alfred Oteng-Yeboah and their co-authors. So why isn't there an international panel of experts for biodiversity?

In aCommentary in Nature last month, Douglas J. McCauley argued that with little evidence to show that market-based conservation works, the time was ripe for a return to the protection of nature for nature's sake. Predictably this has provoked comment, and in Correspondence this week, the issues are aired.

Extensive high sensitivity observations of the cosmic microwave background have been made on an angular scale of 8° covering a substantial fraction of the northern sky. An observed anisotropy in the sky emission at a level of δT/T = 3.7×l0–5 has been detected (T is temperature). This level should strictly be interpreted as an upper limit to the cosmic microwave background fluctuations. It is possibly the direct imprint of density perturbations in the early Universe.