Cellular sensing of extracellular purine nucleosides triggers an innate IFN-β response

Rekha Dhanwani, Mariko Takahashi, Ian T. Mathews, Camille Lenzi, Artem Romanov, Jeramie D. Watrous, Bartijn Pieters, Catherine C. Hedrick, Chris A. Benedict, Joel Linden, Roland Nilsson, Mohit Jain, Sonia Sharma

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Mechanisms linking immune sensing of DNA danger signals in the extracellular environment to innate pathways in the cytosol are poorly understood. Here, we identify a previously unidentified immune-metabolic axis by which cells respond to purine nucleosides and trigger a type I interferon-β (IFN-β) response. We find that depletion of ADA2, an ectoenzyme that catabolizes extracellular dAdo to dIno, or supplementation of dAdo or dIno stimulates IFN-β. Under conditions of reduced ADA2 enzyme activity, dAdo is transported into cells and undergoes catabolysis by the cytosolic isoenzyme ADA1, driving intracellular accumulation of dIno. dIno is a functional immunometabolite that interferes with the cellular methionine cycle by inhibiting SAM synthetase activity. Inhibition of SAM-dependent transmethylation drives epigenomic hypomethylation and overexpression of immune-stimulatory endogenous retroviral elements that engage cytosolic dsRNA sensors and induce IFN-β. We uncovered a previously unknown cellular signaling pathway that responds to extracellular DNA-derived metabolites, coupling nucleoside catabolism by adenosine deaminases to cellular IFN-β production.

Original languageEnglish (US)
Article numberaba3688
JournalScience Advances
Volume6
Issue number30
DOIs
StatePublished - Jul 2020
Externally publishedYes

ASJC Scopus subject areas

  • General

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