Human DNA-PK activates a STING-independent DNA sensing pathway.
Katelyn BurleighJoanna H MaltbaekStephanie CambierRichard GreenMichael GaleRichard C JamesDaniel B StetsonPublished in: Science immunology (2020)
Detection of intracellular DNA by the cGAS-STING pathway activates a type I interferon-mediated innate immune response that protects from virus infection. Whether there are additional DNA sensing pathways, and how such pathways might function, remains controversial. We show here that humans-but not laboratory mice-have a second, potent, STING-independent DNA sensing pathway (SIDSP). We identify human DNA-dependent protein kinase (DNA-PK) as the sensor of this pathway and demonstrate that DNA-PK activity drives a robust and broad antiviral response. We show that the E1A oncoprotein of human adenovirus 5 and the ICP0 protein of herpes simplex virus 1 block this response. We found heat shock protein HSPA8/HSC70 as a target for inducible phosphorylation in the DNA-PK antiviral pathway. Last, we demonstrate that DNA damage and detection of foreign DNA trigger distinct modalities of DNA-PK activity. These findings reveal the existence, sensor, a specific downstream target, and viral antagonists of a SIDSP in human cells.
Keyphrases
- circulating tumor
- cell free
- single molecule
- immune response
- endothelial cells
- heat shock protein
- nucleic acid
- type diabetes
- gene expression
- skeletal muscle
- oxidative stress
- dendritic cells
- adipose tissue
- toll like receptor
- sars cov
- insulin resistance
- genome wide
- single cell
- reactive oxygen species
- anti inflammatory
- heat stress