FASN regulates STING palmitoylation via malonyl-CoA in macrophages to alleviate sepsis-induced liver injury

Biochim Biophys Acta Mol Basis Dis. 2024 Oct;1870(7):167299. doi: 10.1016/j.bbadis.2024.167299. Epub 2024 Jun 13.

Abstract

STING (stimulator of interferon genes) is a critical immunoregulatory protein in sepsis and is regulated by various mechanisms, especially palmitoylation. FASN (fatty acid synthase) is the rate-limiting enzyme to generate cellular palmitic acid (PA) via acetyl-CoA and malonyl-CoA and participates in protein palmitoylation. However, the mechanisms underlying the interaction between STING and FASN have not been completely understood. In this study, STING-knockout mice were used to confirm the pivotal role of STING in sepsis-induced liver injury. Metabolomics confirmed the dyslipidemia in septic mice and patients. The compounds library was screened, revealing that FASN inhibitors exerted a significant inhibitory effect on the STING pathway. Mechanically, the regulatory effect of FASN on the STING pathway was dependent on palmitoylation. Further experiments indicated that the upstream of FASN, malonyl-CoA inhibited STING pathway possibly due to C91 (palmitoylated residue) of STING. Overall, this study reveals a novel paradigm of STING regulation and provides a new perspective on immunity and metabolism.

Keywords: FASN; Macrophages; Malonyl-CoA; STING.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fatty Acid Synthase, Type I* / genetics
  • Fatty Acid Synthase, Type I* / metabolism
  • Humans
  • Lipoylation*
  • Liver / metabolism
  • Liver / pathology
  • Macrophages* / metabolism
  • Male
  • Malonyl Coenzyme A* / metabolism
  • Membrane Proteins* / genetics
  • Membrane Proteins* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Palmitic Acid / pharmacology
  • Sepsis* / complications
  • Sepsis* / drug therapy
  • Sepsis* / metabolism
  • Signal Transduction / drug effects

Substances

  • FASN protein, human
  • Fasn protein, mouse
  • Fatty Acid Synthase, Type I
  • Malonyl Coenzyme A
  • Membrane Proteins
  • Palmitic Acid
  • STING1 protein, human
  • Sting1 protein, mouse