Bacterial small molecule metabolites such as adenosine-diphosphate- d - glycero -β- d - manno -heptose (ADP-heptose) and their derivatives act as effective innate immune agonists in mammals. We show that functional nucleotide-diphosphate-heptose biosynthetic enzymes (HBEs) are distributed widely in bacteria, archaea, eukaryotes, and viruses. We identified a conserved STT R5 motif as a hallmark of heptose nucleotidyltransferases that can synthesize not only ADP-heptose but also cytidine-diphosphate (CDP)– and uridine-diphosphate (UDP)–heptose. Both CDP- and UDP-heptoses are agonists that trigger stronger alpha-protein kinase 1 (ALPK1)–dependent immune responses than ADP-heptose in human and mouse cells and mice. We also produced ADP-heptose in archaea and verified its innate immune agonist functions. Hence, the β- d - manno -heptoses are cross-kingdom, small-molecule, pathogen-associated molecular patterns that activate the ALPK1-dependent innate immune signaling cascade.

中文翻译：

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β-d-甘露庚糖是跨界免疫激动剂


细菌小分子代谢物如腺苷二磷酸-d-甘油-β-d-甘露-庚糖（ADP-庚糖）及其衍生物在哺乳动物中充当有效的先天免疫激动剂。我们发现功能性核苷酸二磷酸庚糖生物合成酶（HBE）广泛分布于细菌、古细菌、真核生物和病毒中。我们发现保守的STT R5基序是七糖核苷酸转移酶的标志，它不仅可以合成ADP-庚糖，还可以合成胞苷二磷酸（CDP）和尿苷二磷酸（UDP）-庚糖。 CDP-和UDP-庚糖都是激动剂，在人和小鼠细胞和小鼠中，它们比ADP-庚糖能引发更强的α蛋白激酶1 (ALPK1)依赖性免疫反应。我们还在古细菌中生产了ADP-庚糖并验证了其先天免疫激动剂功能。因此，β-d-甘露糖-庚糖是跨界、小分子、病原体相关的分子模式，可激活 ALPK1 依赖性先天免疫信号级联。