Human DNA-PK activates a STING-independent DNA sensing pathway
Open Access
- 1 January 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Immunology
- Vol. 5 (43)
- https://doi.org/10.1126/sciimmunol.aba4219
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 ICPO 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.Funding Information
- National Science Foundation (DGE-1256082)
- National Institutes of Health (R21 AI130940)
- National Institutes of Health (T32 GM007270)
- National Institutes of Health (AI104002)
- National Institutes of Health (AI11896)
- National Institutes of Health (AI127463)
- Howard Hughes Medical Institute (55108572)
- Burroughs Wellcome Fund (1013540)
- National Institutes of Health (AI100625)
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