Redox homeostasis maintained by GPX4 facilitates STING activation

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• The stimulator of interferon genes (STING) pathway is essential for innate immunity against pathogens and tumors.
• Cellular redox homeostasis, the balance of oxidation-reduction reactions, is critical for cellular function.
• The precise role of intracellular redox state in controlling STING activation remains largely unknown.

Purpose of the Study:

• To investigate the link between cellular redox homeostasis and STING pathway activation.
• To elucidate the mechanism by which redox state influences STING function.
• To determine the role of glutathione peroxidase 4 (GPX4) in regulating STING signaling.

Main Methods:

• Utilized cell culture models and in vivo studies with herpes simplex virus-1 (HSV-1).
• Assessed STING pathway activation, lipid peroxidation levels, and protein carbonylation.
• Investigated the effect of GPX4 deficiency on STING localization and function.

Main Results:

• GPX4 deficiency led to increased cellular lipid peroxidation, specifically inhibiting the cGAS-STING pathway.
• GPX4 deficiency impaired HSV-1-induced antiviral immune responses and enhanced viral replication in vivo.
• Mechanistically, lipid peroxidation caused by GPX4 inactivation resulted in STING carbonylation at C88, hindering its ER-to-Golgi transport.

Conclusions:

• Cellular redox homeostasis, regulated by GPX4, is required for effective STING activation.
• Lipid peroxidation induced by cellular stress specifically attenuates the STING DNA-sensing pathway.
• GPX4 plays a critical role in facilitating STING activation by maintaining lipid redox homeostasis.