Non-canonical Activation of the DNA Sensing Adaptor STING by ATM and IFI16 Mediates NF-κB Signaling after Nuclear DNA Damage

Mol Cell. 2018 Sep 6;71(5):745-760.e5. doi: 10.1016/j.molcel.2018.07.034.


DNA damage can be sensed as a danger-associated molecular pattern by the innate immune system. Here we find that keratinocytes and other human cells mount an innate immune response within hours of etoposide-induced DNA damage, which involves the DNA sensing adaptor STING but is independent of the cytosolic DNA receptor cGAS. This non-canonical activation of STING is mediated by the DNA binding protein IFI16, together with the DNA damage response factors ATM and PARP-1, resulting in the assembly of an alternative STING signaling complex that includes the tumor suppressor p53 and the E3 ubiquitin ligase TRAF6. TRAF6 catalyzes the formation of K63-linked ubiquitin chains on STING, leading to the activation of the transcription factor NF-κB and the induction of an alternative STING-dependent gene expression program. We propose that STING acts as a signaling hub that coordinates a transcriptional response depending on its mode of activation.

Keywords: DNA damage; IFI16; STING; TRAF6; etoposide; innate immunity; interferon; p53; ubiquitin.

Publication types

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

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / genetics*
  • Cell Line
  • Cell Nucleus / genetics*
  • Cytosol / metabolism
  • DNA / genetics
  • DNA Damage / genetics*
  • HEK293 Cells
  • Humans
  • Immunity, Innate / genetics
  • Keratinocytes / physiology
  • Membrane Proteins / genetics*
  • NF-kappa B / genetics*
  • Nuclear Proteins / genetics*
  • Phosphoproteins / genetics*
  • Poly (ADP-Ribose) Polymerase-1 / genetics
  • Signal Transduction / genetics*
  • Tumor Suppressor Protein p53 / genetics
  • Ubiquitin / genetics
  • Ubiquitin-Protein Ligases / genetics


  • Membrane Proteins
  • NF-kappa B
  • Nuclear Proteins
  • Phosphoproteins
  • STING1 protein, human
  • Tumor Suppressor Protein p53
  • Ubiquitin
  • IFI16 protein, human
  • DNA
  • Ubiquitin-Protein Ligases
  • Poly (ADP-Ribose) Polymerase-1
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins