The STING1-MYD88 complex drives ACOD1/IRG1 expression and function in lethal innate immunity

Feng Chen; Runliu Wu; Jiao Liu; Rui Kang; Jinbao Li; Daolin Tang

doi:10.1016/j.isci.2022.104561

The STING1-MYD88 complex drives ACOD1/IRG1 expression and function in lethal innate immunity

iScience. 2022 Jun 8;25(7):104561. doi: 10.1016/j.isci.2022.104561. eCollection 2022 Jul 15.

Authors

Feng Chen^{1

2}, Runliu Wu², Jiao Liu³, Rui Kang², Jinbao Li¹, Daolin Tang²

Affiliations

¹ Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
² Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
³ DAMP Laboratory, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510510, China.

Abstract

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.

Keywords: Biological sciences; Immune response; Immunology.