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

doi:10.1126/science.adk7314

. 2024 Aug 9;385(6709):678-684.

doi: 10.1126/science.adk7314. Epub 2024 Aug 8.

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

Yue Tang^#¹, Xiaoying Tian^#^{2

3}, Min Wang^#^{1

4}, Yinglu Cui^#¹, Yang She^#², Zhaoxiang Shi⁵, Jiaqi Liu^{2

3}, Huijin Mao^{1

6}, Lilu Liu^{1

6}, Chao Li^{1

6}, Yuwei Zhang¹, Pengwei Li¹, Yue Ma⁷, Jinyuan Sun^{1

6}, Qing Du^{1

6}, Jie Li^{1

6}, Jun Wang^{6

7}, De-Feng Li^{1

6}, Bian Wu^{1

8}, Feng Shao^{2

9

10}, Yihua Chen^{1

6}

Affiliations

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

^# Contributed equally.

PMID: 39116220
DOI: 10.1126/science.adk7314

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

Yue Tang et al. Science. 2024.

. 2024 Aug 9;385(6709):678-684.

doi: 10.1126/science.adk7314. Epub 2024 Aug 8.

Authors

Affiliations

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

^# Contributed equally.

PMID: 39116220
DOI: 10.1126/science.adk7314

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.

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Cited by

Discovery of biosynthetic enzymes for β-D-manno-heptoses across kingdoms: novel agonists for ALPK1/NF-κB-dependent immune response.
Maubach G, Lim MCC, Naumann M. Maubach G, et al. Signal Transduct Target Ther. 2024 Oct 8;9(1):277. doi: 10.1038/s41392-024-02003-y. Signal Transduct Target Ther. 2024. PMID: 39379359 Free PMC article. No abstract available.

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

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

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