NDP‐β‐ d ‐manno‐heptoses are small molecule agonists sensed by the vertebrates to discriminate organisms of different kingdoms

across kingdom, ALPK1, HBE, innate immune, NDP-β-d-manno-heptose, small molecule agonistThe mammalian innate immune system engages germlineencoded pattern recognition receptors (PRRs) to sense the agonists from invading organisms to discriminate 'self' and 'nonself'.1 Those agonists are usually large molecular signatures termed pathogen-associated molecular patterns (PAMPs) or microbe-associated molecular patterns (MAMPs), such as bacterial lipopolysaccharide (LPS) and fungal β-glucan recognized by toll-like receptor 4 or dectin-1, respectively.2,3 Notably, several recent works revealed that, besides the molecular patterns, specific small molecules can also act as agonists that elicit innate immune responses efficiently.4 Several β-d-mannoheptose metabolites involved in the biosynthesis of LPSs have been identified as small molecule agonists that can be recognized by host alpha-protein kinase 1 (ALPK1), with ADP-d-glycero-β-d-manno-heptose (ADP-heptose) and its C-6′′ epimer as the most potent ones.5 Upon binding to ADP-heptose, ALPK1 will undergo conformational changes to phosphorylate TRAF-interacting protein with forkhead-associated domain (TIFA), and then triggers the activation of Nuclear factor kappa B (NF-κB) and inflammation.