Innate immunity, the very first line of defence of our cells, relies on the detection of universal pathogen- or danger-associated signals to launch an inflammatory response. A crucial part of our innate immune system is based on the recognition of out-of-context DNA as an indicator of pathogenic attack, loss of cellular integrity, or homeostatic disruption. The main pathway involved in this detection is the cGAS-STING pathway, that is activated by foreign or out-of-context intracellular DNA and triggers downstream activation of the pro-inflammatory transcription factors IRF3 and NF-kappaB - leading to production of type I interferons and pro-inflammatory cytokines, respectively - and the induction of autophagy. The cGAS-STING axis is central during infection, a key player in anti-tumoral immunity and linked with several autoinflammatory syndromes. The present thesis focuses on unresolved aspects of STING regulation related to its cellular trafficking, both upon initial activation and at signal termination. Two screenings, a microscopy-based one for chemical inhibitors of STING endoplasmic reticulum to Golgi trafficking and a mass spectrometry-based one for interactors implied in this re-localisation, led us to the conclusion that STING relied extensively on essential proteins during this step. Indeed, hits that attenuated STING trafficking also significantly impacted the global cellular state or viability. Furthermore, we pinpointed a potential modulator of STING signalling, ELMOD2, an Arl/Arf-family GTPase activating protein, whose depletion also triggered downstream STING-independent effects, leading to some conflicting results. We therefore moved on to a mutagenesis-based approach which, when combined with high throughput microscopy, could map regions of STING with potentially critical residues involved in trafficking regulation. In parallel, we investigated the mechanisms underlying STING terminal trafficking and its degradation, allowing us to observe colocalization of active phospho-STING molecules with clathrins, as well as with adaptor protein (AP)-1 subunits. We followed STING post-Golgi trafficking with super-high-resolution microscopy and confirmed the presence of STING in clathrin-coated vesicles as well as implication of AP-1 in signalling termination. We were also able to capture STING C-terminal tail in complex with AP-1 and show that AP-1 has greater affinity for phosphorylated STING. Together, our results show that STING phosphorylation at the Golgi, while allowing for downstream IRF3 recruitment and signalling, simultaneously triggers the recruitment of AP-1 and initiates pathway termination. We hence unravelled an elegant feedback mechanism in which STING activation and degradation are directly interconnected, as the residues responsible for IRF3 and AP-1 recruitment partially overlap, indicating a probable concomitant evolution. The data presented in this thesis contribute to extending the knowledge of mechanisms of STING regulation and also shed light on the impact of its cellular localisation on signalling. Furthermore, they give some insights on the importance of the co-evolution of activating and inhibitory mechanisms and embedded feedback loops in innate immune proteins.