STING palmitoylation as a therapeutic target

Cellular & Molecular Immunology
Anne Louise HansenChristian K Holm

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.

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Citations

Dec 7, 2019·Expert Opinion on Drug Discovery·Mohamed Rasheed Gadalla, Michael Veit
Mar 7, 2020·Frontiers in Physiology·Kobina EssandohMatthew J Brody
Nov 15, 2020·Trends in Neurosciences·Bindu D PaulVilhelm A Bohr
Nov 3, 2020·Frontiers in Immunology·Zhaohe LiXin Wang
Mar 4, 2021·Open Biology·Tandrila DasHoward C Hang
Jun 9, 2021·Scientific Reports·Kanoko TakahashiTomohiko Taguchi
Dec 11, 2019·Journal of Medicinal Chemistry·Han ZhangXiao-Li Xu
Sep 2, 2021·ELife·Katarina AkhmetovaIgor Chesnokov

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Methods Mentioned

BETA
GTPase

Clinical Trials Mentioned

NCT03422510
NCT03449524

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