Non-canonical Activation of the DNA Sensing Adaptor STING by ATM and IFI16 Mediates NF-κB Signaling after Nuclear DNA Damage.
Item Type:Journal Article
Citation:Dunphy, G., Flannery, S.M., Almine, J.F., Connolly, D.J., Paulus, C., Jønsson, K.L., Jakobsen, M.R., Nevels, M.M., Bowie, A.G. & Unterholzner, L., Non-canonical Activation of the DNA Sensing Adaptor STING by ATM and IFI16 Mediates NF-κB Signaling after Nuclear DNA Damage., 2018, Molecular cell, 71, 5
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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.
Science Foundation Ireland
Author: Bowie, Andrew; Dunphy, Gillian; Flannery, Sinéad M.; Almine, Jessica F.; Connolly, Dympna J.; Paulus, Christina; Jønsson, Kasper L.; Jakobsen, Martin R.; Nevels, Michael M.; Unterholzner, Leonie
Type of material:Journal Article
Series/Report no:Molecular cell;
Availability:Full text available
Keywords:Detection of etoposide-induced damage by ATM, Innate immunity, DNA damage, Etoposide, Interferon, IFI16, STING, p53, TRAF6, Ubiquitin