Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity

• Published in: Science (American Association for the Advancement of Science) Vol. 348; no. 6240; pp. 1251 - 1255
• Main Authors: Gaudet, Ryan G., Sintsova, Anna, Buckwalter, Carolyn M., Leung, Nelly, Cochrane, Alan, Li, Jianjun, Cox, Andrew D., Moffat, Jason, Gray-Owen, Scott D.
• Format: Journal Article
• Language: English
• Published: Washington American Association for the Advancement of Science 12.06.2015; The American Association for the Advancement of Science
• Subjects: Bacteria; Bacteriology; Cellular biology; Immune systems; Immunity; Immunology; Molecular biology; Monosaccharides; Pathogens; Pathology; Pathways; Proteins; Ribonucleic acids
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aaa4921

Host recognition of pathogen-associated molecular patterns (PAMPs) initiates an innate immune response that is critical for pathogen elimination and engagement of adaptive immunity. Here we show that mammalian cells can detect and respond to the bacterial-derived monosaccharide heptose-1,7-bisphosphate (HBP). A metabolic intermediate in lipopolysaccharide biosynthesis, HBP is highly conserved in Gram-negative bacteria, yet absent from eukaryotic cells. Detection of HBP within the host cytosol activated the nuclear factor κB pathway in vitro and induced innate and adaptive immune responses in vivo. Moreover, we used a genome-wide RNA interference screen to uncover an innate immune signaling axis, mediated by phosphorylation-dependent oligomerization of the TRAF-interacting protein with forkhead-associated domain (TIFA) that is triggered by HBP. Thus, HBP is a PAMP that activates TIFA-dependent immunity to Gram-negative bacteria.