The β- <scp>d</scp> - <i>manno</i> -heptoses are immune agonists across kingdoms
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
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 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.