4-Octyl itaconate restricts STING activation by blocking its palmitoylation

Area of Science:

• Immunology
• Molecular Biology
• Metabolism

Background:

• The cyclic guanosine monophosphate adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is crucial for innate immunity against pathogens.
• Metabolic reprogramming during macrophage activation influences immune responses, but its effect on the cGAS-STING axis is poorly understood.

Purpose of the Study:

• To investigate how metabolic changes affect the cGAS-STING pathway.
• To identify novel regulators and mechanisms of cGAS-STING pathway modulation.

Main Methods:

• Biochemical assays to assess cGAS-STING activation.
• Cellular experiments to evaluate immune responses.
• Mass spectrometry to identify protein modifications.

Main Results:

• 4-octyl itaconate (4-OI), a itaconate derivative, was identified as an inhibitor of cGAS-STING activation.
• 4-OI suppressed cGAS-STING-mediated antiviral immunity and autoimmune inflammation.
• Unlike endogenous itaconate, 4-OI directly alkylates STING at Cys91, preventing its palmitoylation and oligomerization.
• This alkylation represents a novel post-translational modification of STING.

Conclusions:

• 4-octyl itaconate regulates the cGAS-STING pathway through direct alkylation of STING.
• This mechanism highlights a novel crosstalk between metabolic pathways and post-translational modifications in immune regulation.