We are working to understand how cells respond to pathogens, and how these signaling pathways can be harnessed for new potential therapies to treat cancer and autoimmune diseases. Importantly, many aspects of the cellular response to infection remain unknown. Our lab uses an approach where we seek to reconstitute signaling outside of the cell using highly purified components in order to understand the mechanisms that control human immunity.
The cGAS-STING signaling pathway is essential for recognition of DNA released into the cell cytosol during pathogen replication, cellular stress, and cancer. Upon recognition of cytosolic DNA, the enzyme cGAS catalyzes formation of cyclic GMP–AMP (2′3′-cGAMP), a specialized RNA signal that activates the receptor STING to initiate an immune gene expression program. Due to broad tissue tropism and the ability to potently respond to natural small-molecules, cGAS-STING signaling is an emerging target for cancer immunotherapy. Using a structural and biochemical approach, we are working to determine the mechanisms of cGAS-STING signaling:
Our research reveals that cGAS is part of a broad family of largely uncharacterized enzymes, and many cGAS-like signaling pathways remain to be discovered. Human cGAS and a related bacterial protein named DncV are founding members of a novel family of enzymes that we named “cGAS/DncV-like nucleotidyltransferases” (CD-NTases). CD-NTases function by enzymatically synthesizing diverse RNA molecules that serve as signals to amplify a cellular response. In bacteria, CD-NTase enzymes control a form of anti-phage defense named CBASS. We additionally discovered function STING receptors in bacterial CBASS operons revealing that each component of cGAS-STING signaling originated in bacterial anti-phage defense. We are using structural biology and evolutionary-based approaches to understand CD-NTase signaling and the origins of mammalian innate immunity with the broad goals to: