Cellular sensing of extracellular purine nucleosides triggers an innate IFN-β response
Cellular sensing of extracellular purine nucleosides triggers an innate IFN-β response
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DOI：
10.1126/sciadv.aba3688
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发表时间：
2020-07-01
期刊：
影响因子：
13.6
通讯作者：
Sharma, Sonia
中科院分区：
文献类型：
--
作者：
Dhanwani, Rekha;Takahashi, Mariko;Sharma, Sonia
将细胞外环境中DNA危险信号的免疫感知与细胞质中固有途径联系起来的机制尚不清楚。在这里，我们确定了一个以前未被识别的免疫代谢轴，细胞通过该轴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，消耗ADA2（一种将细胞外dAdo分解为dlno的外酶）或补充dAdo或dlno会刺激ifn - β。在ADA2酶活性降低的条件下，dAdo被运输到细胞中，并通过胞质同工酶ADA1进行分解代谢，驱动细胞内dlno的积累。dlno是一种功能性免疫代谢物，通过抑制SAM合成酶活性干扰细胞蛋氨酸循环。sam依赖的转甲基化抑制驱动表观基因组低甲基化和免疫刺激内源性逆转录病毒元件的过表达，这些元件参与细胞质dsRNA传感器并诱导ifn - β。我们发现了一个先前未知的细胞信号通路，该通路响应细胞外dna衍生代谢物，将腺苷脱氨酶的核苷分解代谢与细胞ifn - β的产生结合起来。
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-beta (IFN-beta) response. We find that depletion of ADA2, an ectoenzyme that catabolizes extracellular dAdo to dlno, or supplementation of dAdo or dlno stimulates IFN-beta. Under conditions of reduced ADA2 enzyme activity, dAdo is transported into cells and undergoes catabolysis by the cytosolic isoenzyme ADA1, driving intracellular accumulation of dlno. dlno 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-beta. We uncovered a previously unknown cellular signaling pathway that responds to extracellular DNA-derived metabolites, coupling nucleoside catabolism by adenosine deaminases to cellular IFN-beta production.