Pattern recognition receptors (PRRs) play a vital role in the detection of pathogens and danger signals within the innate immune system. Cyclic GMP-AMP synthase (cGAS) acts as PRR that detects cytosolic dsDNA, a common hallmark of infection. Additionally, cGAS can also recognise host dsDNA that leaks from the mitochondria or nuclei. Detection of dsDNA by cGAS induces the production of the novel cyclic dinucleotide (CDN) 2’3’-cGAMP. 2’3’-cGAMP binds and activates the endoplasmic reticulum resident protein Stimulator of Interferon Genes (STING). Following activation, STING induces a potent type I interferon (type I IFN) response which stimulates transcription of interferon stimulated genes (ISGs). ISGs encode antiviral proteins that facilitates elimination of infected cells. Moreover, the cGAS-STING pathway also activates other non-IFN cellular responses via the transcription factor NF-κB and MAPKs to induce production of proinflammatory cytokines. Recent studies have established the importance of non-IFN STING responses in the context of immunity and disease. From murine models, the pathogenesis of the STING-mediated autoinflammatory disease, appears strongly dependent upon non-IFN response, such as NF-κB activation, rather than IRF3 activation. Similarly, non-IFN STING responses have been found to be critical for protection against HSV-1 viral infection and anti-tumour immunity. This illustrates the importance of studying the mechanism that mediate STINGs non-IFN responses, which can provide the groundwork for new therapeutics development.
Upon activation STING recruits the downstream kinase TANK-binding kinase 1 (TBK1) to induce the production of type I IFNs. Recently, TBK1 and its homologue IκB kinase epsilon (IKKε) have recently been shown to induce the canonical activation of NF-κB in response to STING activation. However, the mechanisms through which TBK1 and IKKε are activated and how they mediate STING responses remain poorly understood. My PhD project will focus on characterising the molecular mechanisms involved in the recruitment and activation of TBK1 and IKKε, and how they regulate downstream non-IFN STING responses.