Type I interferon (IFN) plays essential roles in both spontaneous and iatrogenic tumor immunogenicity. Tumor-derived DNA is recognized by 2’,3’-cyclic GMP-AMP (cGAMP) synthase (cGAS) that is important in tumor immunogenicity. Upon DNA binding, cGAS produces the endogenous second messenger cGAMP that binds to and activates stimulator of IFN genes (STING), a signaling adaptor. cGAMP binding triggers STING trafficking from the endoplasmic reticulum (ER) to perinuclear compartments, with simultaneous activation of serine/threonine-protein kinase TBK1 that in turn phosphorylates the transcription factor IRF3, leading to upregulation of type I interferons. However, where and how TBK1 is activated by STING upon cGAMP stimulation is unclear. Our study focuses on the regulation of cGAMP-stimulated STING trafficking and activation by lipid messengers with essential roles in subcellular protein/membrane trafficking and signaling. Through in vitro signaling reconstitution, we identified a cellular lipid as an essential factor of STING signaling. We found both STING and TBK1 were lipid effectors. Lipid binding not only promotes STING trafficking but also stimulates TBK1 activation. These results reveal a new component of the STING-TBK1 complex that controls cytosolic DNA-stimulated innate immune signaling.

Citation Format: Xiaojun Tan, Conggang Zhang, Zhijian J. Chen. Lipid control of DNA-stimulated innate immunity [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A116.