Non-canonical Activation of the DNA Sensing Adaptor STING by ATM and IFI16 Mediates NF-κB Signaling after Nuclear DNA Damage

Abstract

SummaryDNA 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.

Beyond sensing DNA : a role for cGAS in the detection of extracellular cyclic di‐nucleotides

“…The authors observe that after detection of extracellular CDNs, STING does not translocate to the ERGIC, but instead moves to perinuclear foci that depend on dynein‐mediated transport for their formation (Fig ). This has parallels with other recent findings suggesting that different modes of STING activation exist, which influence its subcellular location and downstream signalling . While the detection of extracellular CDNs causes the activation of TBK1 and IRF3, similar to conventional STING activation during DNA sensing, it is possible that the differential localisation of STING in dynein‐dependent foci could make it susceptible to additional modes of regulation or could induce alternative downstream effects, in addition to the interferon response.…”

A non‐death function of the mitochondrial apoptosis apparatus in immunity

“…Typhimurium) showed CAD dependency. The latter may be linked to a recently discovered “alternative” pathway to STING activation, which has been observed upon experimental induction of DNA damage using the drug etoposide, and which involves formation of a complex containing STING, IFI16, TRAF6, and p53 (Dunphy et al , ). It seems conceivable that a similar complex is formed upon CAD‐dependent DNA damage.…”

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

“…Studies that used the small molecule inhibitors demonstrated that PARP suppression reduces proinflammatory responses or enhances anti-inflammatory functions of macrophages (Haskó et al 2002;Wang et al 2013;Shrestha et al 2016;Dharwal et al 2019). Recent work showed that PARP inhibition in combination with PD-1/PD-L1 blockade could be effective for BRCA1-deficient tumors by activating antigen presenting cells such as dendritic cells via the cGAS-STING pathway (Jiao et al 2017;Ding et al 2018;Dunphy et al 2018). Major effects reported in these studies may reflect PARP1 suppression.…”