DNA sensing unchained

Abstract

In two recent reports in Science, James Chen and colleagues provide compelling evidence that detection of cytosolic DNA triggers the production of a novel second messenger, cyclic GMP-AMP (cGAMP), which in turn activates a signaling pathway that induces type I interferons (IFNs) in a STING-dependent manner. They further unravel a key role for a so far uncharacterized murine protein E330016A19 (human homolog: C6ORF150), now termed cGAMP synthetase (cGAS), to act as the DNA sensor that generates cGAMP.

Figure 1

During infection, microbial DNA gains access to the cell cytoplasm and binds to cGAS. This interaction activates cGAS to synthesize the second messenger cGAMP, which in turn is recognized by ER-localized STING. This event leads to translocation of STING to perinuclear endosomes and recruitment of the kinase TBK1. Finally, this series of events induces the transcriptional upregulation of IFN-β and additional interferon-stimulated genes. It remains to be determined whether this pathway also accounts for accidental recognition of self-DNA in autoimmune and autoinflammatory conditions.