Abstract
Gain-of-function mutations in the STING-encoding gene TMEM173 are central to the pathology of the autoinflammatory disorder STING-associated vasculopathy with onset in infancy (SAVI). Furthermore, excessive activity of the STING signaling pathway is associated with autoinflammatory diseases, including systemic lupus erythematosus and Aicardi–Goutières syndrome (AGS). Two independent studies recently identified pharmacological inhibitors of STING. Strikingly, both types of compounds are reactive nitro-containing electrophiles that target STING palmitoylation, a posttranslational modification necessary for STING signaling. As a consequence, the activation of downstream signaling molecules and the induction of type I interferons were inhibited. The compounds were effective at ameliorating inflammation in a mouse model of AGS and in blocking the production of type I interferons in primary fibroblasts from SAVI patients. This mini-review focuses on the roles of palmitoylation in STING activation and signaling and as a pharmaceutical target for drug development.
Highlights
The intracellular molecule STING (Stimulator of interferon genes, known as MPYS, ERIS, MITA, and TMEM173) is indispensable for the induction of type I interferons (IFNs, e.g., IFNα/β) in response to infection with DNA-based viruses[1–3] and with bacteria such as Listeria monocytogenes,[4] as demonstrated using both in vitro and in vivo experimental approaches
STING has recently been reported to play a role in neuro-inflammation.[82]. The contribution of STING is
STING acts as a sensor of cyclic dinucleotides
Summary
Anne Louise Hansen[1], Kojiro Mukai[2], Francisco J. Excessive activity of the STING signaling pathway is associated with autoinflammatory diseases, including systemic lupus erythematosus and Aicardi–Goutières syndrome (AGS). Two independent studies recently identified pharmacological inhibitors of STING. Both types of compounds are reactive nitrocontaining electrophiles that target STING palmitoylation, a posttranslational modification necessary for STING signaling. The compounds were effective at ameliorating inflammation in a mouse model of AGS and in blocking the production of type I interferons in primary fibroblasts from SAVI patients. This mini-review focuses on the roles of palmitoylation in STING activation and signaling and as a pharmaceutical target for drug development.
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