Nature https://doi.org/10.1038/s41586-019-0998-5, https://doi.org/10.1038/s41586-019-1000-2 & https://doi.org/10.1038/s41586-019-1006-9 (2019)

STING is a dimeric endoplasmic reticulum–resident adaptor that is activated by the recognition of cytosolic DNA and the generation of cyclic GMP-AMP (cGAMP), which ultimately results in the production of type I interferons. In Nature, Chen and colleagues present three studies that reveal how binding of cGAMP alters the conformation of STING to trigger its oligomerization and translocation to the Golgi and interactions with the kinase TBK1. Cryo–electron microscopy reveals that cGAMP induces allosteric conformational changes in STING to form tetramers. While apo-STING can bind to dimeric TBK1, the STING-phosphorylation site is not accessible to either kinase domain of TBK1. Instead, cGAMP-induced tetramerization of STING is needed to position tandem TBK1 kinases for trans-phosphorylation of one STING dimer by the TBK1 dimer bound to an adjacent STING dimer. Such oligomerization then facilitates recruitment and activation of the transcription factor IRF3. A separate study identifies a cGAS–STING-dependent non-canonical autophagy pathway activated by cytosolic DNA and DNA viruses. Neither TBK1 nor IRF3 is required for this process, suggestive of a primordial anti-viral function of STING that is independent of interferons.