Cell biological insights into human STING variants.

Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER)-localized transmembrane protein. STING induces type I interferon and inflammatory responses against a variety of double-stranded DNA (dsDNA) viruses, which is critical for limiting their infection and replication. In certain settings where self-DNAs (genomic or mitochondrial DNA) emerge in the cytosol or when intracellular membrane traffic is impaired, STING becomes activated and triggers inflammation, which may contribute to the pathogenesis of various autoinflammatory and neurodegenerative diseases, including COPA syndrome and Parkinson's disease. The human STING gene exhibits genetic heterogeneity with R232, HAQ (R71H-G230A-R293Q), and H232 being the most common variants, along with population stratification. A very recent study has shown that HAQ, not R232 or H232, mediates complete clinical protection in the pathogenesis of COPA syndrome. These results reveal, for the first time, the distinct activities of the major variants in the context of the pathogenesis of autoinflammatory diseases. Besides these major variants, there exist minor pathogenic STING variants that cause an autoinflammatory disease called STING-associated vasculopathy with onset in infancy (SAVI). This review summarizes recent insights into human STING variants and their inflammatory activities.Key words: innate immunity, STING variants, COPA syndrome, membrane traffic, the Golgi.