Redox homeostasis maintained by GPX4 facilitates STING activation

Nat Immunol. 2020 Jul;21(7):727-735. doi: 10.1038/s41590-020-0699-0. Epub 2020 Jun 15.

Abstract

Stimulator-of-interferon genes (STING) is vital for sensing cytosolic DNA and initiating innate immune responses against microbial infection and tumors. Redox homeostasis is the balance of oxidative and reducing reactions present in all living systems. Yet, how the intracellular redox state controls STING activation is unclear. Here, we show that cellular redox homeostasis maintained by glutathione peroxidase 4 (GPX4) is required for STING activation. GPX4 deficiency enhanced cellular lipid peroxidation and thus specifically inhibited the cGAS-STING pathway. Concordantly, GPX4 deficiency inhibited herpes simplex virus-1 (HSV-1)-induced innate antiviral immune responses and promoted HSV-1 replication in vivo. Mechanistically, GPX4 inactivation increased production of lipid peroxidation, which led to STING carbonylation at C88 and inhibited its trafficking from the endoplasmic reticulum (ER) to the Golgi complex. Thus, cellular stress-induced lipid peroxidation specifically attenuates the STING DNA-sensing pathway, suggesting that GPX4 facilitates STING activation by maintaining redox homeostasis of lipids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbolines / pharmacology
  • Cells, Cultured
  • DNA, Viral / immunology
  • Disease Models, Animal
  • Endoplasmic Reticulum / metabolism
  • Female
  • Fibroblasts
  • Golgi Apparatus / metabolism
  • HEK293 Cells
  • Herpes Simplex / immunology*
  • Herpes Simplex / virology
  • Herpesvirus 1, Human / genetics
  • Herpesvirus 1, Human / immunology
  • Homeostasis / immunology
  • Humans
  • Immunity, Innate
  • Lipid Peroxidation / genetics
  • Lipid Peroxidation / immunology
  • Macrophages, Peritoneal / cytology
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / metabolism
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Nucleotidyltransferases / metabolism
  • Oxidation-Reduction
  • Oximes / pharmacology
  • Phospholipid Hydroperoxide Glutathione Peroxidase / antagonists & inhibitors
  • Phospholipid Hydroperoxide Glutathione Peroxidase / genetics
  • Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism*
  • Primary Cell Culture
  • Protein Carbonylation / immunology
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Sulfonamides / pharmacology
  • THP-1 Cells
  • Virus Replication / immunology

Substances

  • Carbolines
  • DNA, Viral
  • FIN56 compound
  • Membrane Proteins
  • Oximes
  • RSL3 compound
  • STING1 protein, human
  • Sting1 protein, mouse
  • Sulfonamides
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • glutathione peroxidase 4, mouse
  • Nucleotidyltransferases
  • cGAS protein, human
  • cGAS protein, mouse