β-d-manno-heptoses 是跨王国的免疫激动剂。

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2024-08-08 DOI:10.1126/science.adk7314

Yue Tang, Xiaoying Tian, Min Wang, Yinglu Cui, Yang She, Zhaoxiang Shi, Jiaqi Liu, Huijin Mao, Lilu Liu, Chao Li, Yuwei Zhang, Pengwei Li, Yue Ma, Jinyuan Sun, Qing Du, Jie Li, Jun Wang, De-feng Li, Bian Wu, Feng Shao, Yihua Chen

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引用次数: 0

摘要

细菌的小分子代谢物，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体内可作为有效的先天性免疫激动剂。我们发现，功能性核苷酸-二磷酸-庚糖生物合成酶（HBEs）广泛分布于细菌、古生菌、真核生物和病毒中。我们发现了庚糖核苷酸转移酶的一个保守 STTR5 基序，它不仅能合成 ADP-庚糖，还能合成胞苷-二磷酸（CDP）-庚糖和尿苷-二磷酸（UDP）-庚糖。与 ADP-庚糖相比，CDP-庚糖和 UDP-庚糖都是能在人和小鼠细胞及小鼠体内引发更强的α-蛋白激酶 1（ALPK1）依赖性免疫反应的激动剂。我们还在古菌中产生了 ADP-庚糖，并验证了其先天性免疫激动剂功能。因此，β-d-甘露庚糖是一种跨领域、小分子、与病原体相关的分子模式，可激活 ALPK1 依赖性先天性免疫信号级联。

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The β-d-manno-heptoses are immune agonists across kingdoms

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.

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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