Research
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. ADP-heptose is synthesized from d-sedoheptulose 7-phosphate (S7P) via a four-step relay catalyzed by NDP-heptose biosynthetic enzymes (HBEs) with isomerase, kinase, phosphatase, and nucleotidyltransferase activities. Knowledge of β-d-manno-heptose biosynthesis is limited to bacteria, and non-bacterial HBEs have not been described yet. Prof. CHEN Yihua’s Lab at the Institute of Microbiology, Chinese Academy of Sciences (IMCAS) expanded the distribution of HBEs and the structural diversity of NDP-heptoses by collaborating with Prof. SHAO Feng (National Institute of Biological Sciences, Beijing) and Prof. WU Bian (IMCAS). They found that the β-d-manno-heptoses are cross-kingdom small molecule pathogen-associated molecular patterns that activate the alpha-protein kinase 1 (ALPK1)-dependent innate immune signaling cascade. This work was published in Science.
Prof. CHEN Yihua and colleagues discovered that functional HBEs are distributed widely in bacteria, archaea, eukaryotes, and viruses. A conserved STTR5 motif was identified 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 ALPK1-dependent immune responses than ADP-heptose in human and mouse cells and mice. ADP-heptose was also produced in archaea and verified its innate immune agonist functions.
Evolutionary analysis implied that, after deuterostomes lost the ability to synthesize β-d-manno-heptoses, some vertebrates, including mammals, evolved ALPK1s as specific receptors for immunological recognition of β-d-manno-heptoses produced by members of different kingdoms. Considering the vast number and diverse origins of HBEs, the authors believe that heptose metabolites play many more biological roles than currently known. This study updates the distribution of the β-d-manno-heptose metabolites and sets the stage for future studies regarding the structural diversity of HBE-related heptose metabolites and their biological roles in different kingdoms.
This work was supported by projects from the Ministry of Science and Technology of the People’s Republic of China, the National Natural Science Foundation of China, and the Chinese Academy of Sciences Programs.
Figure: Organisms of different kingdoms can synthesize β-d-manno-heptoses that are sensed by vertebrate immune receptors. (image by Prof. CHEN Yihua’s group)