Silencing of DNA by cGAS

The cGAS-STING pathway has emerged as an essential innate immune sensing system, which recognises DNA and triggers potent innate immune responses. In addition to DNA from various pathogens, cGAS can also recognise endogenous DNA in micronuclei, chromatin fragments, mitochondrial DNA and DNA derived from retrotransposons, resulting in the formation of membraneless cGAS-DNA phase-separated organelles. 

Regulation of DNA sensing by cGAS is critical in preventing autoinflammatory diseases such as Aicardi-Goutières syndrome. Although cGAS mediated induction of IFN by cytoplasmic DNA is extensively studied, it remains unknown how the pathway is regulated in the phase-separated organelles to allow efficient immune responses without resulting in pathological aggregates.

I will carry out mass-spectrometry guided CRISPR-Cas9 and siRNA screens to identify cellular proteins that regulate the cGAS-STING pathway. In addition to providing a better understanding of fundamental aspects of cGAS functions within the cell, improved insights into these aspects will inform the development of potential therapeutic strategies in many auto-inflammatory diseases.