Non-canonical activation of the DNA sensing adaptor STING by ATM and IFI16 mediates NF-κB signalling after nuclear DNA damage

Gillian Dunphy, Sinéad M Flannery, Jessica F Almine, Dympna J Connolly, Christina Paulus, Kasper L Jonsson, Martin R Jakobsen, Michael Martin Nevels, Andrew G Bowie, Leonie Unterholzner

Research output: Contribution to journalArticlepeer-review

391 Citations (Scopus)
15 Downloads (Pure)

Abstract

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.
Original languageEnglish
Article numbere5
Pages (from-to)745-760
Number of pages22
JournalMolecular Cell
Volume71
Issue number5
DOIs
Publication statusPublished - 6 Sept 2018

Keywords

  • Innate immunity
  • DNA damage
  • Etoposide
  • Interferon
  • IFI16
  • STING
  • p53
  • TRAF6
  • Ubiquitin

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