STING palmitoylation as a therapeutic target

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.

Keywords: Inflammation; Interferonopathies; Palmitoylation; SAVI; STING.

Fig. 1

NO₂-FAs and nitrofuran derivatives that inhibit STING signaling. The red arrows indicate the sites that can participate in a Michaels addition reaction with STING cysteines

Fig. 2

Proposed chemical reaction between the electrophilic nitrofuran (left), nitroalkene-containing inhibitors (right) and STING Cys 88 and 91

Fig. 3

Alkylation of STING cysteines 88/91 inhibits STING palmitoylation and signaling