Stimulator of Interferon Genes (STING) is an adaptor protein critical for downstream signaling during recognition of mislocalized cytosolic DNA. STING activation requires recognition of a unique second messenger 2′–5′, 3′–5′ cyclic GMP–AMP (2′3′ cGAMP) synthesized by the pathogen recognition receptor cyclic GMP–AMP synthase (cGAS). Due to its broad expression in most tissues, and ability to respond to different endogenous and foreign small molecules, STING is emerging as a promising drug target for cancer immunotherapy and treatment of autoimmune diseases. However, it remains unknown how the single adaptor protein STING controls distinct transcriptional outputs leading to production of type I interferon, proinflammatory cytokine responses or autophagy. Here we present surprising evidence for the ancient origins of the cGAS-STING signaling pathway by discovery of bacterial cGAS-like enzymes and complete functional cGAS-STING pathways in lower metazoans. Our previous structural data demonstrate that human and metazoan STING proteins share a common architecture that couples ligand binding with conformational changes and allows signal activation. However, it remained unclear how alternative STING conformations control different downstream signaling outputs, and which motifs are responsible for recruitment of the downstream factors controlling each pathway. We have now combined a phylogenetic and biochemical approach to explain the conserved elements that regulate STING downstream signaling events. Our analysis identifies new immune pathway-specific regulatory motifs acquired by distinct STING species, and we are currently focused on identifying the recruited factors important for controlling human STING signaling. Together, our results explain the molecular basis for distinct STING downstream signaling, and provide new insights for the rational design of STING pathway-specific therapeutics.

Citation Format: Carina C. de Oliveira Mann, David S. King, Philip J. Kranzusch. STING acquired species-specific motifs to control alternative immune responses [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 B150.