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

• Published in: Science advances 2020-07, Vol.6 (30), p.eaba3688-eaba3688
• Main Authors: Dhanwani, Rekha, Takahashi, Mariko, Mathews, Ian T, Lenzi, Camille, Romanov, Artem, Watrous, Jeramie D, Pieters, Bartijn, Hedrick, Catherine C, Benedict, Chris A, Linden, Joel, Nilsson, Roland, Jain, Mohit, Sharma, Sonia
• Format: Article
• Language: English
• Subjects: Immunology; Medicin och hälsovetenskap; SciAdv r-articles; Signal Transduction
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aba3688

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.