STING immune activation and regulation by phosphatidylinositol 4-phosphate-associated components

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.