{Reference Type}: Journal Article
{Title}: The β-d-manno-heptoses are immune agonists across kingdoms.
{Author}: Tang Y;Tian X;Wang M;Cui Y;She Y;Shi Z;Liu J;Mao H;Liu L;Li C;Zhang Y;Li P;Ma Y;Sun J;Du Q;Li J;Wang J;Li DF;Wu B;Shao F;Chen Y;
{Journal}: Science
{Volume}: 385
{Issue}: 6709
{Year}: 2024 Aug 9
{Factor}: 63.714
{DOI}: 10.1126/science.adk7314
{Abstract}: Bacterial small molecule metabolites such as adenosine-diphosphate-d-glycero-β-d-manno-heptose (ADP-heptose) and their derivatives act as effective innate immune agonists in mammals. We show that functional nucleotide-diphosphate-heptose biosynthetic enzymes (HBEs) are distributed widely in bacteria, archaea, eukaryotes, and viruses. We identified a conserved STTR5 motif as a hallmark of heptose nucleotidyltransferases that can synthesize not only ADP-heptose but also cytidine-diphosphate (CDP)- and uridine-diphosphate (UDP)-heptose. Both CDP- and UDP-heptoses are agonists that trigger stronger alpha-protein kinase 1 (ALPK1)-dependent immune responses than ADP-heptose in human and mouse cells and mice. We also produced ADP-heptose in archaea and verified its innate immune agonist functions. Hence, the β-d-manno-heptoses are cross-kingdom, small-molecule, pathogen-associated molecular patterns that activate the ALPK1-dependent innate immune signaling cascade.