| First Author | Zhou P | Year | 2018 |
| Journal | Nature | Volume | 561 |
| Issue | 7721 | Pages | 122-126 |
| PubMed ID | 30111836 | Mgi Jnum | J:264436 |
| Mgi Id | MGI:6196443 | Doi | 10.1038/s41586-018-0433-3 |
| Citation | Zhou P, et al. (2018) Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose. Nature |
| abstractText | 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. |
