In eukaryotic cells, DNA from microbial pathogens in the cytosol is detected by various pattern recognition receptors (PRRs). Cyclic GMP–AMP (cGAMP) synthase (cGAS) functions as a PRR in many cell types, including immune-engaged cells. After binding to cytosolic DNA, cGAS catalyses the synthesis of cGAMP, which activates the downstream adaptor stimulator of IFN genes (STING). In its resting state, STING localises to the ER, and upon activation, it translocates to the perinuclear region, where it recruits other factors necessary for the production of type I interferons responsible for the elimination of microbial pathogens. Although STING is an essential component of the pathogen response, the reason for the translocation of its activated state is not known. In this work, Xinqi Liu and colleagues (Ji et al., 2021) identify apoptosis-linked gene 2 (ALG2) as a negative regulator of STING trafficking and DNA-induced immune response. The authors find an enhanced immune response in ALG2-knockout THP-1 cells compared to that in wild-type cells, with ALG2 knockout also strongly promoting STING translocation to the perinuclear region in response to cGAMP. Co-immunoprecipitation experiments confirm the interaction between ALG2 and the C-terminal tail of STING. Furthermore, the function of ALG2 in regulating STING trafficking is dependent on calcium signalling. Taken together, these findings demonstrate a role for ALG2 in regulating STING translocation and immune response, with consequences for autoimmune diseases involving abnormal activation of STING.
