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

• 成果类型: Article
• 署名作者: Tang, Yue; Tian, Xiaoying; Wang, Min; Cui, Yinglu; She, Yang; Shi, Zhaoxiang; Liu, Jiaqi; Mao, Huijin; Liu, Lilu; Li, Chao; Zhang, Yuwei; Li, Pengwei; Ma, Yue; Sun, Jinyuan; Du, Qing; Li, Jie; Wang, Jun; Li, De-feng; Wu, Bian; Shao, Feng; Chen, Yihua
• 署名单位: Chinese Academy of Sciences; Institute of Microbiology, CAS; National Institute of Biological Sciences, Beijing; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Chinese Academy of Medical Sciences - Peking Union Medical College; Shenyang Pharmaceutical University; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; Institute of Microbiology, CAS; Beijing University of Chemical Technology; Tsinghua University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12644
• DOI: 10.1126/science.adk7314
• 发表日期: 2024-08-09
• 页码: 678-684
• 关键词: innate; RECOGNITION; biosynthesis; pathways

摘要

Bacterial small molecule metabolites such as adenosine-diphosphate-d-glycero-beta-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 beta-d-manno-heptoses are cross-kingdom, small-molecule, pathogen-associated molecular patterns that activate the ALPK1-dependent innate immune signaling cascade.