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

Dunphy, Gillian and Flannery, Sinead and Almine, Jessica and Connolly, Dympna and Paulus, Christina and Jønsson, Kasper and Jakobsen, Martin and Nevels, Michael and Bowie, Andrew and Unterholzner, Leonie (2018) Non-canonical activation of the DNA sensing adaptor STING by ATM and IFI16 mediates NF-κB signalling after nuclear DNA damage. Molecular Cell, 71 (5). pp. 745-760. ISSN 1097-2765

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 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.