Research ArticleINNATE IMMUNITY

Human DNA-PK activates a STING-independent DNA sensing pathway

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Science Immunology  24 Jan 2020:
Vol. 5, Issue 43, eaba4219
DOI: 10.1126/sciimmunol.aba4219

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Sensing DNA sans STING

Stimulator of interferon genes (STING) plays a central role in sensing intracellular DNA in mammalian cells. By studying the ability of adenoviral oncoprotein E1A to repress DNA sensing in human cells, Burleigh et al. have found a STING-independent intracellular DNA sensing pathway that relies on DNA-dependent protein kinase (DNA-PK). They report that DNA-PK–dependent DNA sensing pathway is not activated by cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), a cyclic dinucleotide synthesized that is sensed by STING. Furthermore, DNA-PK–dependent DNA sensing is intact in STING-deficient cells. In-depth molecular characterization of this pathway is needed to understand how DNA-PK and STING-dependent DNA sensing pathways function in tandem to sense and respond to intracellular DNA.

Abstract

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.

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