Cell biological insights into human STING variants

Abstract

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.

Keywords: COPA syndrome; STING variants; innate immunity; membrane traffic; the Golgi.

Fig. 1

Major human STING variants a, Domain organization of human STING and positions of amino acid substitutions in its variants: transmembrane domain (blue), the cGAMP binding region (green), and the C-terminal tail (CTT) (beige). b, STING genotypes found in the five ethnic groups in the 1000 Genomes Project (phase III) (Patel et al., 2017).

Fig. 2

Activation of WT and H232 STING in COPA disease In normal conditions, WT (R232) and H232 translocate to the Golgi with the COP-II machinery, whereas HAQ remains localized at the ER. WT (R232) and H232 are then retrieved back to the ER with the COP-I machinery, ensuring their predominant localizations at the ER. In the conditions where pathogenic α-COP is expressed, WT (R232) and H232 cannot be retrieved back to the ER, leading to their activations at the TGN. SAVI-STINGs have a reduced affinity to Surf4, making them poor cargos for the COP-I transport.

Fig. 3

Amino acid substitutions in SAVI-STING variants a, The vertical lines indicate the positions of the amino acid substitutions in SAVI-STING. b, The SAVI mutations (red) are superimposed on the three-dimensional structure of a wild-type STING dimer modeled using AlphaFold3.