摘要：SummaryACOD1 (also known as IRG1) has emerged as a regulator of immunometabolism that operates by producing metabolite itaconate. Here, we report a key role of STING1 (also known as STING and TMEM173) in mediating ACOD1 expression in myeloid cells in response to toll-like receptor (TLR) signaling. The activation of STING1 through exogenous cyclic dinucleotides (e.g., 3′3′-cGAMP) or endogenous gain-of-function mutation (e.g., V155M) enhances lipopolysaccharide-induced ACOD1 expression and itaconate production in macrophages and monocytes, whereas the deletion of STING1 blocks this process. The adaptor protein MYD88, instead of DNA sensor cyclic GMP-AMP synthase (CGAS), favors STING1-dependent ACOD1 expression. Mechanistically, MYD88 directly blocks autophagic degradation of STING1 and causes subsequent IRF3/JUN-mediated ACOD1 gene transcription. Consequently, the conditional deletion of STING1 in myeloid cells fails to produce ACOD1 and itaconate, thereby protecting mice against endotoxemia and polymicrobial sepsis. Our results, therefore, establish a direct link between TLR4 signaling and ACOD1 expression through the STING1-MYD88 complex during septic shock.Graphical abstractDisplay OmittedHighlights•The MYD88-STING1 protein complex is required for lipopolysaccharide (LPS)-induced ACOD1 expression•The MYD88-STING1 protein complex prevents autophagic degradation of STING1•The IRF3-JUN transcription factor complex favors ACOD1 upregulation•STING1-mediated itaconate production promotes experimental sepsisBiological sciences; Immunology; Immune response
