No 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 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 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.

Stimulator-of-interferon gene (STING) is a vital element of the innate immune system against DNA viruses. Optimal activation of STING is crucial for maintaining immune homeostasis and eliminating invading viruses, and the oligomerization of STING is an essential prerequisite for STING activation. However, the mechanism of cGAMP-induced STING oligomerization in ER remains unclear. Selenoproteins are crucial for various physiological processes. Here, we identified that the endoplasmic reticulum (ER)-located transmembrane selenoprotein K (SELENOK) was induced during virus infection and facilitated innate immune responses against herpes simplex virus-1 (HSV-1). Mechanistically, SELENOK interacts with STING in the ER and promotes STING oligomerization, which in turn promotes its translocation from the ER to the Golgi. Consequently, Selenok deficiency suppresses STING-dependent innate responses and facilitates viral replication in vivo. Thus, the control of STING activation by selenium-mediated SELENOK expression will be a priming therapeutic strategy for the treatment of STING-associated diseases.

No abstract

NLRP3 inflammasome, as the archetypical molecular driver of inflammatory response, plays crucial roles in host defense and the maintenance of cell homeostasis. The demethylation of trimethylation of lysine 9 at histone 3 (H3K9me3, the repressive mark for euchromatic genes) is a prerequisite for the transcription of most genes. However, whether H3K9 demethylation is required for the induction of proinflammatory cytokines remains unknown. Here, we show that histone demethylase lysine-specific demethylase 4B (KDM4B) mediates demethylation of H3K9me3 at the Nlrp3 promoter to induce NLRP3 expression. It therefore selectively enhances NLRP3 inflammasome activation without affecting NF-κB activation. Concordantly, Kdm4b deficiency and the selective KDM4 inhibitor ML324 both inhibit NLRP3 inflammasome activation and ameliorate NLRP3-dependent inflammatory diseases in vivo. Moreover, high glucose upregulates KDM4B to promote NLRP3 inflammasome activation and IL-1β secretion, and therefore aggravates viral infection-induced aberrant inflammation. Therefore, we determine the role of H3K9me3 demethylation in initiating inflammation, identify KDM4B as an epigenetic enhancer of NLRP3, and suggest modulating H3K9me3 might be an anti-inflammatory strategy with better selectivity.