Oleic Acid Dissolves cGAS-DNA Phase Separation to Inhibit Immune Surveillance

Area of Science:

• Biochemistry
• Immunology
• Cell Biology

Background:

• Phase separation (PS) is crucial for biological processes, including immune surveillance.
• The dissolution mechanisms of phase separation, particularly in the context of immunity, remain largely unexplored.

Purpose of the Study:

• To investigate the role of metabolites in dissolving phase separation.
• To determine if oleic acid (OA) can dissolve cyclic GMP-AMP synthase (cGAS)-DNA phase separation and affect immune surveillance.

Main Methods:

• Metabolite screening was performed to identify compounds that dissolve cGAS-DNA condensates.
• The effect of oleic acid (OA) on intracellular cGAS-DNA phase separation and DNA-induced immune activation was assessed.
• The impact of OA on cGAS-mediated antiviral and anticancer immune responses was evaluated.

Main Results:

• Long-chain fatty acids, including oleic acid (OA), were found to markedly dissolve cGAS-DNA condensates formed via phase separation.
• OA effectively revoked intracellular cGAS-PS and DNA-induced activation.
• OA treatment attenuated cGAS-mediated antiviral and anticancer immunosurveillance.

Conclusions:

• Oleic acid dissolves cGAS-DNA phase separation, thereby inhibiting immune surveillance.
• This study establishes a link between metabolism and immunity through the dissolution of phase separation.
• The findings suggest that targeting phase separation dissolution could be a potential therapeutic strategy for immune-related diseases.