Abstract：
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 STTR5 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.
摘要：
细菌小分子代谢物如腺苷-二磷酸-d-甘油-β-d-甘露糖-庚糖(ADP-庚糖)及其衍生物在哺乳动物中作为有效的先天免疫激动剂。我们表明，功能性核苷酸-二磷酸-庚糖生物合成酶（HBEs）广泛分布在细菌中，古细菌,真核生物,和病毒。我们确定了保守的STTR5基序作为庚糖核苷酸转移酶的标志，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。在人和小鼠细胞和小鼠中,与ADP-庚糖相比,CDP-和UDP-庚糖都是引发更强的α-蛋白激酶1(ALPK1)依赖性免疫应答的激动剂。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-甘露聚糖是交叉王国，小分子,激活ALPK1依赖性先天免疫信号级联的病原体相关分子模式。
