Pattern recognition receptors (PRRs) have evolved to sense microbial DNA and elicit protective immunity as part of the innate immune system. The major sensor of cytosolic double stranded (ds)DNA is the enzyme cGAS (cyclic GMP-AMP synthase). Upon binding of dsDNA, cGAS produces a cyclic di-nucleotide molecule, cGAMP. STING (Stimulator of Interferon Genes) is then activated by cGAMP to produce key immune mediators, such as interferons (IFNs) and pro-inflammatory cytokines to elicit a protective anti-viral immune response. We are exploring the role of the cGAS-STING pathway in the context of infection, autoimmunity (e.g. Lupus), autoinflammation and anti-cancer immunity by investigating the fundamental mechanisms that control STING signalling and trafficking responses.
We recently identified IKK, as a new molecule in the STING signalling pathway that is able to elicit pro-inflammatory immune responses via the transcription factor, NF-B (Balka et al., Cell Reports 2022). We discovered that IKK works redundantly along with TBK1, the major effector kinase downstream of STING. We are now further examining the roles of IKK in STING-mediated immune responses. In addition, we are employing a number of high-end imaging modalities (e.g. Airyscan confocal, Lattice light-sheet) in combination with fluorescent STING reporter systems to examine STING trafficking in both fixed and live immune cells. These high-resolution approaches will illuminate previously unrecognised aspects of STING trafficking and its relation to STING-mediated cellular processes.