Species-specific self-DNA detection mechanisms by mammalian cyclic GMP-AMP synthases.
Kenta MosallanejadStephanie N KennedyKristin M BahledaKailey M SlavikWen ZhouApurva A GovandeDustin C HancksPhilip J KranzuschJonathan C KaganPublished in: Science immunology (2023)
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.
Keyphrases
- circulating tumor
- single molecule
- cell free
- single cell
- endothelial cells
- nucleic acid
- innate immune
- induced apoptosis
- dna damage
- magnetic resonance
- escherichia coli
- cell therapy
- type diabetes
- metabolic syndrome
- cell proliferation
- immune response
- genetic diversity
- bone marrow
- adipose tissue
- transcription factor
- sensitive detection
- binding protein
- pi k akt