Activation of cGAS/STING by the Caspase-Activated DNAse

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The ability to recognize infections and injury are of key importance to an organism. Myeloid cells are particularly well-equipped for this purpose and have been most extensively studied. However, the principal capacity of recognizing pathogens and of mounting some response is probably common to at least most nucleated human cells. The cGAS/STING-axis of DNA-recognition and signalling is shaping up as a module of very broad importance in host defence. cGAS-recognition of double-stranded DNA was first reported in the defence reaction against cytosolic DNA-viruses, but recent work has considerably extended this concept to first a nuclear presence of cGAS and, secondly, a role in the recognition of self-DNA. I here propose that the caspase-activated DNAse (CAD) has a role in generating a cGAS-ligand and activating STING in response to infection, and that this mechanism is of importance in the primary recognition of pathogens by non-professional immune cells such as epithelial cells. CAD is better known as the enzyme that degrades genomic DNA during apoptosis but a non-apoptotic activation of CAD is now accepted. We have reported that infection of human and mouse cells with multiple pathogens causes the non-lethal activation of CAD and have since tested for a role of CAD in a number of biological fields and signalling pathways. Importantly, we have collected evidence that CAD in these situations can generate a cGAS-ligand and initiate STING-signalling. This signalling pathway is activated in metastasis, in senescence and in infection and drives for instance a type I-interferon response. In this project we will endeavour to understand the molecular basis of this pathway and its role in infections. We have some preliminary data and will investigate in detail which potential cGAS-ligands are generated by CAD-activity. In the second part we will test which one of these potential ligands plays which role in the activation of cGAS. In the third part of the project we will study how infectious agents without a plausible cGAS-ligand, such as extracellular bacteria and RNA-viruses, may activate cGAS/STING through sub-lethal signals in the mitochondrial apoptosis pathway and the activation of CAD. The notion that sub-lethal signals in the apoptosis machinery can be used to signal immune alert is novel but has substantial experimental support. The concept that this signalling works through the infliction of damage to the genomic DNA by CAD may be surprising but is in our view backed up by very strong evidence. We believe that we have discovered a new, versatile and potentially very important signalling system in host defence. In this project we will substantially advance in its detailed understanding.