ALG2 regulates type I interferon responses by inhibiting STING trafficking
Wangsheng Ji, Lianfei Zhang, Xiaoyu Xu, Xinqi Liu
Abstract
Stimulator of IFN genes (STING), an endoplasmic reticulum (ER) signaling adaptor, is essential for the type I interferon response to cytosolic double-stranded DNA. Translocation from the ER to perinuclear vesicles following cyclic GMP-AMP (cGAMP) binding is a critical step for STING to activate downstream signaling molecules, which leads to the production of interferon and pro-inflammatory cytokines. Here, we found that apoptosis-linked gene 2 (ALG2, also known as PDCD6) suppressed STING signaling induced by herpes simplex virus-1 (HSV-1) infection or cGAMP presence. Knockout of ALG2 markedly increased the expression of type I interferons upon cGAMP treatment or HSV-1 infection in THP-1 monocytes. Mechanistically, ALG2 associated with the C-terminal tail of STING and inhibited its trafficking from the ER to the perinuclear region. Furthermore, the ability of ALG2 to coordinate Ca2+ was crucial for its regulation of STING trafficking and DNA-induced innate immune responses. This work suggests that ALG2 is involved in DNA-induced innate immune responses by regulating STING trafficking.