Project description
Delving into the immune mechanism of antiviral control
The immune system has evolved a DNA-sensing mechanism that allows it to respond to viruses and even target cancer cells. This mechanism involves the activation of cyclic GMP–AMP synthase (cGAS), which subsequently interacts with the stimulator of interferon genes (STING) effector to initiate immune response. The key objective of the EU-funded STARPAC project is to dissect the complex process of STING activation and function and identify the key players. Moreover, researchers wish to delineate how STING activation is implicated in the identification and tackling of RNA viruses. Results have the potential to identify novel targets for the design of antiviral strategies.
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 activation
2. Identify and target regulators of PI4P biology to increase STING activity
3. 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.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
3584 CS Utrecht
Netherlands