STING palmitoylation as a therapeutic target

Area of Science:

• Immunology
• Molecular Biology
• Drug Discovery

Background:

• Gain-of-function mutations in TMEM173 (STING) cause STING-associated vasculopathy with onset in infancy (SAVI).
• Overactive STING signaling contributes to autoinflammatory diseases such as systemic lupus erythematosus and Aicardi-Goutières syndrome (AGS).
• STING palmitoylation is a crucial posttranslational modification for its signaling pathway activation.

Purpose of the Study:

• To review the role of STING palmitoylation in STING activation and signaling.
• To highlight STING palmitoylation as a pharmaceutical target for autoinflammatory diseases.
• To discuss recent advancements in the development of STING inhibitors.

Main Methods:

• Identification of pharmacological STING inhibitors by two independent studies.
• Characterization of inhibitors as reactive nitro-containing electrophiles targeting STING palmitoylation.
• Assessment of inhibitor efficacy in a mouse model of AGS and primary fibroblasts from SAVI patients.

Main Results:

• Inhibitors successfully blocked STING palmitoylation, downstream signaling, and type I interferon induction.
• Compounds ameliorated inflammation in a mouse model of Aicardi-Goutières syndrome.
• Inhibitors effectively blocked type I interferon production in primary fibroblasts from SAVI patients.

Conclusions:

• STING palmitoylation is a critical regulatory step and a viable therapeutic target.
• Pharmacological inhibition of STING palmitoylation demonstrates therapeutic potential for SAVI, AGS, and related autoinflammatory conditions.
• Novel STING inhibitors represent a promising avenue for drug development in autoinflammatory diseases.