4-octyl itaconate as a metabolite derivative inhibits inflammation via alkylation of STING.

Abstract

The Krebs cycle-derived metabolite itaconate, whose production is catalyzed by immune response gene 1 (IRG1), has potential to link immunity and metabolism in activated macrophages through alkylation or competitive inhibition of target proteins. In support of this, our previous study demonstrated that the stimulator of interferon genes (STING) signaling platform functions as a hub in macrophage immunity and has a profound impact on the prognosis of sepsis. Interestingly, we find that itaconate, an endogenous immunomodulator, can significantly inhibit the activation of STING signaling. Moreover, 4-octyl itaconate (4-OI), which is a permeable itaconate derivative, can alkylate cysteine sites 65, 71, 88, and 147 of STING, thereby inhibiting its phosphorylation. Furthermore, itaconate and 4-OI inhibit the production of inflammatory factors in sepsis models. Our results broaden the knowledge on the role of the IRG1-itaconate axis in immunomodulation and highlight itaconate and its derivatives as potential therapeutic agents in sepsis.

• Authors: Weizhen Li, Yangguang Li, Jiaqi Kang, Haiyang Jiang, Wenbin Gong, Lijuan Chen, Cunxia Wu, Mingda Liu, Xiuwen Wu, Yun Zhao, Jianan Ren
• Journal: Cell reports (Cell Rep) Vol. 42 Issue 3 Pg. 112145 (03 28 2023) ISSN: 2211-1247 [Electronic] United States
• PMID: 36862550 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• 4-octyl itaconate
• itaconic acid
• Proteins
• Succinates
• Membrane Proteins

Topics

• Humans
• Alkylation
• Inflammation (drug therapy)
• Proteins (metabolism)
• Succinates (pharmacology, metabolism)
• Membrane Proteins