title: INNATE IMMUNITY. Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity.
abstract: 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 facto 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.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Canada M5S 1A8.
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Gaudet
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Canada M5S 1A8.
authors.forename: Anna
authors.initials: A
authors.lastname: Sintsova
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Canada M5S 1A8.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Buckwalter
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Canada M5S 1A8.
authors.forename: Nelly
authors.initials: N
authors.lastname: Leung
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Canada M5S 1A8.
authors.forename: Alan
authors.initials: A
authors.lastname: Cochrane
authors.affiliation: Vaccine Program, National Research Council, Ottawa, ON, Canada K1A 0R6.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Li
authors.affiliation: Vaccine Program, National Research Council, Ottawa, ON, Canada K1A 0R6.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cox
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Canada M5S 1A8. Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto, Toronto, Canada M5S 3E1.
authors.forename: Jason
authors.initials: J
authors.lastname: Moffat
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Canada M5S 1A8. scott.gray.owen@utoronto.ca.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Gray-Owen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D019117:Burkholderia / Q000276:immunology; D003600:Cytosol / Q000737:chemistry / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology; D005408:Flagellin / Q000276:immunology; D005820:Genetic Testing; D006090:Gram-Negative Bacteria / Q000276:immunology* / Q000378:metabolism; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D019169:Jurkat Cells; D016328:NF-kappa B / Q000276:immunology; D009344:Neisseria gonorrhoeae / Q000276:immunology; D009345:Neisseria meningitidis / Q000276:immunology; D034622:RNA Interference; D013403:Sugar Phosphates / Q000032:analysis / Q000276:immunology* / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000276:immunology / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016328:NF-kappa B; D013403:Sugar Phosphates; C446759:TIFA protein, human; D048029:TNF Receptor-Associated Factor 6; D005408:Flagellin