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

Sci Immunol. 2020 Jan 24;5(43):eaba4219. doi: 10.1126/sciimmunol.aba4219.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenoviridae
  • Adenovirus E1A Proteins / immunology
  • Animals
  • Cell Line
  • DNA-Activated Protein Kinase / immunology*
  • Herpes Simplex / immunology
  • Herpesvirus 1, Human
  • Humans
  • Immediate-Early Proteins / immunology
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Mice
  • Ubiquitin-Protein Ligases / immunology


  • Adenovirus E1A Proteins
  • Immediate-Early Proteins
  • Membrane Proteins
  • STING1 protein, human
  • Ubiquitin-Protein Ligases
  • Vmw110 protein, Human herpesvirus 1
  • DNA-Activated Protein Kinase