STARPAC · STING immune activation and regulation by phosphatidylinositol 4-phosphate-associated components
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-09-01 → 2023-10-03
- EU contribution
- €187,572
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
STING immune activation and regulation by phosphatidylinositol 4-phosphate-associated components
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.
Data: CORDIS, © European Union
Project objective
The immune response to cytosolic DNA is crucial for preventing tumour formation and virus infection. This response critically depends on the cGAS-STING pathway, which detects cytosolic self-DNA present in tumour cells and viral DNA. STING can also detect cytosolic self-DNA induced by upon RNA virus infections, and numerous RNA viruses have evolved strategies to disable STING.STING activation is a complex process that requires various post-translational modifications, leading to STING trafficking and activation at the Golgi apparatus. STING activation induces the transcription of genes that promote immune cell recruitment. Aberrant STING regulation may lead to virus infections, inflammatory disorders, and tumour formation. Many of the regulators involved in STING activation are unknown. To identify host factors regulating STING activity, I recently performed a genome-wide CRISPRi screen (Luteijn et al, 2019, Nature). I found many novel genes involved in STING activation, including the Golgi protein ACBD3. This protein localizes the phospholipid phosphatidylinositol 4-phosohate (PI4P) to the Golgi membrane by recruiting the PI4P kinase PI4KB. My preliminary work revealed that STING activation in the Golgi critically depends on ACBD3 and PI4P. Remarkably, ACBD3 and other PI4P-associated factors are also targeted during infection by certain RNA viruses. It is completely unknown how ACBD3 and PI4P distribution affect STING activity, and if PI4P hijacking by RNA viruses modifies the STING-induced immune response.This project has 3 main objectives:1.Define the role of ACBD3 and PI4KB expression and function on STING activation2.Identify and target regulators of PI4P biology to increase STING activity3.Define the role of PI4P hijacking by RNA viruses on STING immune evasion Understanding how ACBD3 and other PI4P-associated factors regulate STING will lead to the identification of novel therapeutic targets to combat tumours, virus infections, and inflammation.
Original text from CORDIS.
Participants
- UNIVERSITEIT UTRECHT · UtrechtCoordinatorNetherlands
Links
Data: CORDIS, © European Union