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

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<mark>Journal publication date</mark>6/09/2018
<mark>Journal</mark>Molecular Cell
Issue number5
Volume71
Number of pages16
Pages (from-to)745-760
Publication statusPublished
Original languageEnglish

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.