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
La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Sci Adv. 2020 Jul 22;6(30):eaba3688. doi: 10.1126/sciadv.aba3688. eCollection 2020 Jul.
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.
细胞外环境中DNA危险信号的免疫感知与胞质溶胶中固有途径之间的联系机制尚不清楚。在这里，我们确定了一条以前未被识别的免疫代谢轴，通过该轴细胞对嘌呤核苷作出反应并触发I型干扰素-β（IFN-β）反应。我们发现，将胞外腺苷脱氨酶2（ADA2）耗尽，该酶可将细胞外脱氧腺苷（dAdo）分解代谢为二氢肌苷（dIno），或者补充dAdo或dIno，都会刺激IFN-β产生。在ADA2酶活性降低的条件下，dAdo被转运到细胞中，并由胞质同工酶ADA1进行分解代谢，促使dIno在细胞内积累。dIno是一种功能性免疫代谢物，它通过抑制S-腺苷甲硫氨酸（SAM）合成酶的活性来干扰细胞的甲硫氨酸循环。对SAM依赖性转甲基作用（SAM-dependent transmethylation）的抑制会导致表观基因组低甲基化，并使参与胞质双链RNA传感器并诱导IFN-β的免疫刺激内源性逆转录病毒元件过表达。我们发现了一条以前未知的细胞信号通路，该通路对细胞外DNA衍生的代谢物作出反应，将腺苷脱氨酶的核苷分解代谢与细胞IFN-β的产生联系起来。
