Stimulator of interferon genes protein (STING) S162A mutant (STING S162A)

Stimulator of Interferon Genes (STING), encoded by the STING1 gene, is a critical transmembrane protein located in the endoplasmic reticulum that functions as a central adaptor in the innate immune response to cytosolic DNA (UniProt: Q86WV6). The Human STING S162A mutant features a specific substitution of Serine with Alanine at position 162 within the cyclic dinucleotide (CDN) binding domain (Liu et al., 2014, Nature Communications). This mutation is of significant pharmacological interest because it confers sensitivity to DMXAA (Vadimezan), a small-molecule agonist that activates murine STING but fails to activate the wild-type human protein (Kim et al., 2013, Science). Upon activation by ligands such as CDNs or DMXAA, the STING S162A mutant undergoes a conformational change and translocates to the Golgi apparatus, where it recruits and activates TANK-binding kinase 1 (TBK1). This recruitment leads to the phosphorylation of Interferon Regulatory Factor 3 (IRF3), ultimately driving the transcription of Type I interferons and pro-inflammatory cytokines (Gao et al., 2013, Cell). In a clinical context, the STING pathway is a major target for cancer immunotherapy, aimed at turning “cold” tumors “hot” by stimulating the recruitment of dendritic cells and T-cells. However, therapeutic use of STING agonists must be carefully managed to avoid systemic inflammation or cytokine release syndrome. The S162A mutant remains a vital tool for researchers to bridge the gap between murine models and human drug development (Conlon et al., 2013, Journal of Immunology).

Other names

TMEM173 S162AERIS S162AMITA S162AMPYS S162ATransmembrane protein 173 S162AHuman STING S162A

Agonist-induced activation of the STING-TBK1-IRF3 signaling pathway