Chen Feng, Wu Runliu, Liu Jiao, Kang Rui, Li Jinbao, Tang Daolin
Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
iScience. 2022 Jun 8;25(7):104561. doi: 10.1016/j.isci.2022.104561. eCollection 2022 Jul 15.
ACOD1 (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.
ACOD1（也称为IRG1）已成为一种免疫代谢调节因子，通过产生代谢物衣康酸发挥作用。在此，我们报告了STING1（也称为STING和TMEM173）在介导髓系细胞中ACOD1表达以响应Toll样受体（TLR）信号方面的关键作用。通过外源性环二核苷酸（如3'3'-cGAMP）或内源性功能获得性突变（如V155M）激活STING1可增强巨噬细胞和单核细胞中脂多糖诱导的ACOD1表达和衣康酸产生，而删除STING1则会阻断这一过程。衔接蛋白MYD88而非DNA传感器环鸟苷酸-腺苷酸合成酶（CGAS）有利于STING1依赖性ACOD1表达。从机制上讲，MYD88直接阻断STING1的自噬降解，并导致随后的IRF3/JUN介导的ACOD1基因转录。因此，髓系细胞中STING1的条件性缺失无法产生ACOD1和衣康酸，从而保护小鼠免受内毒素血症和多重微生物败血症的侵害。因此，我们的研究结果在脓毒性休克期间通过STING1-MYD88复合物建立了TLR4信号与ACOD1表达之间的直接联系。
