title: Hexokinase Is an Innate Immune Receptor for the Detection of Bacterial Peptidoglycan.
abstract: Degradation of Gram-positive bacterial cell wall peptidoglycan in macrophage and dendritic cell phagosomes leads to activation of the NLRP3 inflammasome, a cytosolic complex that regulates processing and secretion of interleukin (IL)-1β and IL-18. While many inflammatory responses to peptidoglycan are mediated by detection of its muramyl dipeptide component in the cytosol by NOD2, we report here that NLRP3 inflammasome activation is caused by release of N-acetylglucosamine that is detected in the cytosol by the glycolytic enzyme hexokinase. Inhibition of hexokinase by N-acetylglucosamine causes its dissociation from mitochondria outer membranes, and we found that this is sufficient to activate the NLRP3 inflammasome. In addition, we observed that glycolytic inhibitors and metabolic conditions affecting hexokinase function and localization induce inflammasome activation. While previous studies have demonstrated that signaling by pattern recognition receptors can regulate metabolic processes, this study shows that a metabolic enzyme can act as a pattern recognition receptor. PAPERCLIP.
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Wolf
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Reyes
authors.affiliation: Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Liang
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Becker
authors.affiliation: Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Division of Pediatric Infectious Diseases, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shimada
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Wheeler
authors.affiliation: Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Hee Cheol
authors.initials: HC
authors.lastname: Cho
authors.affiliation: Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Narcis I
authors.initials: NI
authors.lastname: Popescu
authors.affiliation: Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: K Mark
authors.initials: KM
authors.lastname: Coggeshall
authors.affiliation: Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Division of Pediatric Infectious Diseases, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Moshe
authors.initials: M
authors.lastname: Arditi
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: david.underhill@csmc.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Underhill
mesh_terms: D000107:Acetylation; D000117:Acetylglucosamine / Q000378:metabolism; D000818:Animals; D001408:Bacillus anthracis / Q000378:metabolism; D002473:Cell Wall / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D006019:Glycolysis; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D010457:Peptidoglycan / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*
chemical_list: D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D010457:Peptidoglycan; D011971:Receptors, Immunologic; D006593:Hexokinase; D011188:Potassium; D000117:Acetylglucosamine