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

• Published in: Science (American Association for the Advancement of Science) 2024-08, Vol.385 (6709), p.678-684
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Animals; Archaea - immunology; Bacteria; Eukaryotes; Flagellin; Heptoses; Humans; Immune response; Immune system; Immunity, Innate; Innate immunity; Kinases; Lipopolysaccharides; Mice; Nucleotides; Nucleotidyltransferases - metabolism; Pathogens; Prokaryotes; Vertebrates
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.adk7314

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