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

Kenta Mosallanejad, Stephanie N. Kennedy, Kristin M. Bahleda, Kailey M. Slavik, Wen Zhou, Apurva A. Govande, Dustin C. Hancks, Philip J. Kranzusch, Jonathan C. Kagan

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)eabp9765
JournalScience Immunology
Issue number79
StatePublished - Jan 20 2023

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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