2. Academic Validation
  3. Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose

Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose

  • Nature. 2018 Sep;561(7721):122-126. doi: 10.1038/s41586-018-0433-3.
Ping Zhou 1,  Yang She 1 2 3,  Na Dong 4,  Peng Li 1,  Huabin He 1,  Alessio Borio 5,  Qingcui Wu 1,  Shan Lu 1,  Xiaojun Ding 6,  Yong Cao 1,  Yue Xu 1,  Wenqing Gao 1,  Mengqiu Dong 1,  Jingjin Ding 1 2,  Da-Cheng Wang 2,  Alla Zamyatina 5,  Feng Shao 7 8 9
Affiliations

Affiliations

  • 1 National Institute of Biological Sciences, Beijing, China.
  • 2 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 3 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
  • 4 College of Animal Science and Technology, China Agricultural University, Beijing, China.
  • 5 Department of Chemistry, University of Natural Resources and Life Sciences, Vienna, Austria.
  • 6 Beijing Mingde Zhengkang Technologies Co., Ltd., Beijing, China.
  • 7 National Institute of Biological Sciences, Beijing, China. shaofeng@nibs.ac.cn.
  • 8 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. shaofeng@nibs.ac.cn.
  • 9 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China. shaofeng@nibs.ac.cn.
PMID: 30111836 DOI: 10.1038/s41586-018-0433-3
Abstract

Immune recognition of pathogen-associated molecular patterns (PAMPs) by Pattern Recognition Receptors often activates proinflammatory NF-κB signalling1. Recent studies indicate that the Bacterial metabolite D-glycero-β-D-manno-heptose 1,7-bisphosphate (HBP) can activate NF-κB signalling in host cytosol2-4, but it is unclear whether HBP is a genuine PAMP and the cognate pattern recognition receptor has not been identified. Here we combined a transposon screen in Yersinia pseudotuberculosis with biochemical analyses and identified ADP-β-D-manno-heptose (ADP-Hep), which mediates type III secretion system-dependent NF-κB activation and cytokine expression. ADP-Hep, but not Other heptose metabolites, could enter host cytosol to activate NF-κB. A CRISPR-Cas9 screen showed that activation of NF-κB by ADP-Hep involves an ALPK1 (alpha-kinase 1)-TIFA (TRAF-interacting protein with forkhead-associated domain) axis. ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. The crystal structure of the N-terminal domain of ALPK1 and ADP-Hep in complex revealed the atomic mechanism of this ligand-receptor recognition process. HBP was transformed by host adenylyltransferases into ADP-heptose 7-P, which could activate ALPK1 to a lesser extent than ADP-Hep. ADP-Hep (but not HBP) alone or during Bacterial infection induced Alpk1-dependent inflammation in mice. Our findings identify ALPK1 and ADP-Hep as a pattern recognition receptor and an effective immunomodulator, respectively.

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