Species-specific self-DNA detection mechanisms by mammalian cyclic GMP-AMP synthases

Abstract

The mechanisms by which innate immune receptors mediate self-nonself discrimination are unclear. In this study, we found species-specific molecular determinants of self-DNA reactivity by cyclic guanosine monophosphate–adenosine monophosphate (GMP–AMP) synthase (cGAS). Human cGAS contained a catalytic domain that was intrinsically self-DNA reactive and stimulated interferon responses in diverse cell types. This reactivity was prevented by an upstream amino (N)-terminal domain. The cGAS proteins from several nonhuman primate species exhibited a similar pattern of self-DNA reactivity in cells, but chimpanzee cGAS was inactive even when its amino-terminal domain was deleted. In contrast, the N terminus of mouse cGAS promoted self-DNA reactivity. When expressed within tumors, only self-DNA–reactive cGAS proteins protected mice from tumor-induced lethality. In vitro studies of DNA- or chromatin-induced cGAS activation did not reveal species-specific activities that correlate with self-DNA reactivity observed in macrophages. Cell biological analysis revealed that self-DNA reactivity by human cGAS, but not mouse cGAS, correlated with localization to mitochondria. We found that epitope tag positions affected self-DNA reactivity in cells and that DNA present in cell lysates undermines the reliability of cGAS biochemical fractionations. These studies reveal species-specific diversity of cGAS functions, even within the primate lineage, and highlight experimental considerations for the study of this innate immune receptor.

ATM and ATR, two central players of the DNA damage response, are involved in the induction of systemic acquired resistance by extracellular DNA, but not the plant wound response

“…Taken together, the beforementioned observations open promising perspectives, but they do not present a basis to exclude that a process connected to the DDR is contributing to the activation of immune signalling by extracellular DNA fragments. The DDR evolved for the repair of an organism´s own genome and thus, it seems plausible to assume that some of the involved elements work best for the own DNA but only partially when dealing with nonself-DNA; similar to the recently discovered differences among the mechanisms that control the self-DNA reactivity of cGAS molecules from different primates ( 46 ). We used mutant lines of atr and atm because both kinases are conserved among plants and mammals and well-known for their central role in the coordination of the DDR ( 139 ).…”

“…Nevertheless, it appears difficult to envision receptors able to differentiate between the fragmented genomes of two closely related plant species. For mammals, the differential activation of murine versus human plasmacytoid Dendritic Cells (pdCs) by single-stranded RNA of Human Immunodeficiency Virus Type 1 (HIV-1) could be attributed to TLR 7 and 8 ( 134 ) and most recently, species-specific differences have been discovered among the mechanism used for DNA binding by cGAS from different mammalian species ( 46 ). Still, the only mammalian dsDNA sensor known to distinguish DNA from organisms belonging to different phylogenetic groups seems to be TLR9, which binds preferably DNA that is rich in unmethylated CpG motifs and thus allows for differential immune responses to bacterial and viral DNA versus genomic DNA of eukaryotes ( 135 – 137 ), i.e., a differentiation at the level of domains.…”

“…We conclude that intact DDR machinery is required to activate the SA-dependent plant immunity response to extracellular DNA whereas an as-yet unknown mechanism controls the species-specific perception of DNA fragments as DAMPs that activate the JA-dependent wound response. Future studies will have to investigate whether the recently reported different mechanisms by which cGAS molecules from different mammalian species recognise their respective self-DNA ( 46 ) provide a starting point to identify the mechanisms that allow for a differential recognition of DNA in a single plant species.…”

“…Both the WR and SAR usually lead to a systemic so-called ‘pattern-triggered immunity’ (PTI) even after local attack. Considering the different roles of DAMPs and PAMPs in the activation of PTI, it seems reasonable to assume that self- and nonself DNA is sensed as a DAMP or a PAMP respectively, similar to the roles that place DNA sensors such as cGAS and TLR9 inflammasome-forming DNA receptors at the centre of mammalian innate immunity to pathogens, cancer and damage by abiotic factors ( 6 , 15 , 45 , 46 ).…”

Evolutionary immunology to explore original antiviral strategies

“…Authors exploring comparative immunology have noted that, while signalling pathways tend to be conserved between species, the receptors sensing infection are less conserved and evolve rapidly, as do the effector molecules regulated by these pathways (e.g. [15][16][17][18]). Hence, innate immunity pathways exhibit an information bottleneck, akin to the bottleneck in gene expression corresponding to the establishment of the axis of the embryo during development.…”