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

Ping Zhou, Yang She, Na Dong, Peng Li, Huabin He, Alessio Borio, Qingcui Wu, Shan Lu, Xiaojun Ding, Yong Cao, Yue Xu, Wenqing Gao, Mengqiu Dong, Jingjin Ding, Da-Cheng Wang, Alla Zamyatina and Feng Shao ()
Additional contact information
Ping Zhou: National Institute of Biological Sciences
Yang She: National Institute of Biological Sciences
Na Dong: China Agricultural University
Peng Li: National Institute of Biological Sciences
Huabin He: National Institute of Biological Sciences
Alessio Borio: University of Natural Resources and Life Sciences
Qingcui Wu: National Institute of Biological Sciences
Shan Lu: National Institute of Biological Sciences
Xiaojun Ding: Beijing Mingde Zhengkang Technologies Co., Ltd.
Yong Cao: National Institute of Biological Sciences
Yue Xu: National Institute of Biological Sciences
Wenqing Gao: National Institute of Biological Sciences
Mengqiu Dong: National Institute of Biological Sciences
Jingjin Ding: National Institute of Biological Sciences
Da-Cheng Wang: Institute of Biophysics, Chinese Academy of Sciences
Alla Zamyatina: University of Natural Resources and Life Sciences
Feng Shao: National Institute of Biological Sciences

Nature, 2018, vol. 561, issue 7721, 122-126

Abstract: 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.

Keywords: Kinase Alpha (ALPK1); Pseudotuberculosis; Allen PK; Enterotoxigenic E. Coli (ETEC); Diffusely Adherent E. Coli (DAEC) (search for similar items in EconPapers)
Date: 2018
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Citations: View citations in EconPapers (2)

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DOI: 10.1038/s41586-018-0433-3

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