Abstract

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 bene fi cial 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 homeostasis 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.

                             Schematic representation of the roles of myristic acid and N-myristoylation in STING  activation