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

Affiliations
  • 1State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 2National Institute of Biological Sciences, Beijing 102206, China.
  • 3Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 102206, China.
  • 4College of New Materials and Chemical Engineering, Beijing Institute of Petrochemical Technology, Beijing 102617, China.
  • 5School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 117004, China.
  • 6University of Chinese Academy of Sciences, Beijing 100049, China.
  • 7CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 8College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, PR China.
  • 9Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China.
  • 10New Cornerstone Science Laboratory, Shenzhen 518054, China.

Published on:

August 8, 2024

Abstract

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.

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