In healthy cells, DNA is confined to certain intracellular spaces, including the nucleus. Upon cellular damage, for example from a virus infection, bacterial infection, or tumor formation, DNA is mislocalized to the cytosol. This mislocalized DNA is a danger signal that is recognized by innate immune sensors, including the cGAS-STING pathway. Upon activation, this pathway mounts a potent immune response aimed to clear the pathogen (in case of a viral of bacterial infection) or cancerous cell. The critical role of the STING-mediated immune response against various danger signals is well-recognized, as examplified by the observation that mice lacking cGAS or STING are more sensitive to bacterial infections, tumor formation and virus infections. In addition, therapeutic targeting of STING in individuals suffering from tumours can activate the immune system and promote tumour regression. On the other hand, overactivation of the cGAS-STING pathway can lead to age-related diseases, including Alzhemer's disease, Parkinson, and other age-related chronic inflammatory conditions. Finally, individuals with mutations in STING or associated genes suffer from auto-inflammatory conditions including Aicardi-Goutières Syndrome and STING-associated vasculopathy with onset in infancy.
STING activation is a tightly regulated multistep process that is aimed to prevent unwanted activation (which could lead to auto-inflammatory diseases) but at the same time must robustly activate the immune system in case of a real threat. How STING is regulated is not well understood. A better understanding of STING regulation will provide new targets to combat a wide variety of diseases, including auto-inflammatory conditions, cancer, and ageing.
In this project, we investigated how STING is regulated by phosphatidyl inositol-4 phosphate (PI4P), a lipid present at specific locations within the cell. In addition, we investigated how manipulating PI4P with (FDA-approved) drugs can redirect the immune response by STING. Finally, we tested whether viruses that use PI4P for replication (such as rhinoviruses) can tamper with STING activation by changing the intracellular distribution of PI4P.
Conclusion of the action
We found that targeting PI4P and PI4P-associated factors can alter immune activation by affecting the intracellular distribution of STING. Furthermore, we show (FDA-approved) compounds that target PI4P can dampen or promote immune activation by STING, and we thus provide novel therapeutic targets for clinically relevant diseases.
