Structural Insights into STING Signaling

Since its discovery 12 years ago, the stimulator of interferon genes (STING) pathway has attracted the intense focus of top cell biologists, biochemists, and structural biologists, due to its unique activation mechanisms and broad implications in cancer, aging, and autoimmunity. The STING pathway is an essential innate immune signaling cascade responsible for the sensing of aberrant cytosolic double-stranded DNA (dsDNA), which is a hallmark of cancer and viral infection. Erroneous STING activation can exacerbate many autoimmune and inflammatory syndromes. Therefore, it is remarkable how rapidly, effectively, and specifically the STING pathway responds to a myriad of threats while generally maintaining immune homeostasis. Here we review high-impact structural work that collectively paints a picture of STING signaling with atomic resolution. The elegant molecular mechanisms not only give clues to how STING has evolved to distinguish between self and foreign, but they also enable development of novel therapeutics to treat STING-related diseases.