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

3 Scopus citations

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.

Original languageEnglish (US)
Article numbereabp9765
JournalScience Immunology
Volume8
Issue number79
DOIs
StatePublished - Jan 2023

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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