Enzyme biochemistry and innate immune signaling
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 critical 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 mechanistic and structural underpinnings that control human immunity.
In humans, the cGAS-STING signaling pathway is essential for immunity to diverse pathogens. Upon recognition of foreign DNA, the enzyme cGAS catalyzes formation of cyclic GMP–AMP (cGAMP), a second-messenger cyclic dinucleotide 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, STING is a rapidly emerging target for cancer immunotherapy. Using a structural and biochemical approach, we are working to determine the mechanisms of cGAS-STING signaling:
- How do cellular and pathogen co-factors regulate cGAS enzymatic activity?
- What role do alternative STING conformations play in controlling downstream transcriptional responses?
Immunology Structure and Evolution
Our previous work illuminates a surprisingly ancient origin of human cGAMP signaling by discovery of cGAS-like enzymes in bacteria and complete cGAS-STING pathways in lower metazoans. Using these systems as a new frame of reference, we have provided a mechanistic rationale for the unique potency of the modern human cGAMP second-messenger. We are continuing to use an evolutionary-based approach to understand cellular signaling within the human innate immune system with the major goals to:
- Determine how evolutionary forces have shaped signaling specificity within the human immune system
- Develop cellular assays to broadly identify new regulatory layers controlling pathogen recognition and tumor immunity