Myristic acid as a checkpoint to regulate STING-dependent autophagy and interferon responses by promoting N-myristoylation

Stimulator of interferon gene (STING)-triggered autophagy is crucial for the host to eliminate invading pathogens and serves as a self-limiting mechanism of STING-induced interferon (IFN) responses. Thus, the mechanisms that ensure the beneficial effects of STING activation are of particular importance. Herein, we show that myristic acid, a type of long-chain saturated fatty acid (SFA), specifically attenuates cGAS-STING-induced IFN responses in macrophages, while enhancing STING-dependent autophagy. Myristic acid inhibits HSV-1 infection-induced innate antiviral immune responses and promotes HSV-1 replication in mice in vivo. Mechanistically, myristic acid enhances N-myristoylation of ARF1, a master regulator that controls STING membrane trafficking. Consequently, myristic acid facilitates STING activation-triggered autophagy degradation of the STING complex. Thus, our work identifies myristic acid as a metabolic checkpoint that contributes to immune home-ostasis by balancing STING-dependent autophagy and IFN responses. This suggests that myristic acid and N-myristoylation are promising targets for the treatment of diseases caused by aberrant STING activation.

Automated summary

This study demonstrates that STING-triggered autophagy plays a crucial role in eliminating pathogens and limiting STING-induced interferon responses. Specifically, myristic acid attenuates IFN responses while enhancing STING-dependent autophagy, contributing to immune homeostasis. Mechanistically, myristic acid promotes N-myristoylation of ARF1, which controls STING membrane trafficking and enhances autophagy degradation of the STING complex. Targeting myristic acid and N-myristoylation could be a promising approach for treating diseases caused by aberrant STING activation.