Final published version
Licence: CC BY: Creative Commons Attribution 4.0 International License
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Non-canonical activation of the DNA sensing adaptor STING by ATM and IFI16 mediates NF-κB signalling after nuclear DNA damage
AU - Dunphy, Gillian
AU - Flannery, Sinead
AU - Almine, Jessica
AU - Connolly, Dympna
AU - Paulus, Christina
AU - Jønsson, Kasper
AU - Jakobsen, Martin
AU - Nevels, Michael
AU - Bowie, Andrew
AU - Unterholzner, Leonie
PY - 2018/9/6
Y1 - 2018/9/6
N2 - 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 signalling complex which includes the tumour suppressor p53 and the E3 ubiquitin ligase TRAF6. TRAF6 catalyses 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 signalling hub that co-ordinates a transcriptional response depending on its mode of activation.
AB - 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 signalling complex which includes the tumour suppressor p53 and the E3 ubiquitin ligase TRAF6. TRAF6 catalyses 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 signalling hub that co-ordinates a transcriptional response depending on its mode of activation.
KW - innate immunity
KW - DNA damage
KW - etoposide
KW - interferon
KW - IFI16
KW - STING
KW - p53
KW - TRAF6
KW - ubiquitin
U2 - 10.1016/j.molcel.2018.07.034
DO - 10.1016/j.molcel.2018.07.034
M3 - Journal article
VL - 71
SP - 745
EP - 760
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 5
ER -