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Publication Abstract from PubMed

Immune recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors often activates proinflammatory NF-kappaB signalling(1). Recent studies indicate that the bacterial metabolite D-glycero-beta-D-manno-heptose 1,7-bisphosphate (HBP) can activate NF-kappaB signalling in host cytosol(2-4), 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-beta-D-manno-heptose (ADP-Hep), which mediates type III secretion system-dependent NF-kappaB activation and cytokine expression. ADP-Hep, but not other heptose metabolites, could enter host cytosol to activate NF-kappaB. A CRISPR-Cas9 screen showed that activation of NF-kappaB 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.

Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose.,Zhou P, She Y, Dong N, Li P, He H, Borio A, Wu Q, Lu S, Ding X, Cao Y, Xu Y, Gao W, Dong M, Ding J, Wang DC, Zamyatina A, Shao F Nature. 2018 Aug 15. pii: 10.1038/s41586-018-0433-3. doi:, 10.1038/s41586-018-0433-3. PMID:30111836^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.