Selective activation of PFKL suppresses the phagocytic oxidative burst
| Autor: | Maria A. Voronkova, Madison P. Cooper, Justin M. Kollman, Kebing Yu, Kim Newton, Steven T. Staben, Eric M. Lynch, Taylur P. Ma, Dewakar Sangaraju, Vishva M. Dixit, Neri Amara, Zijuan Lai, Matthew Bogyo, Bradley A. Webb, Nobuhiko Kayagaki |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Neutrophils Phosphofructokinase-1 Pentose phosphate pathway General Biochemistry Genetics and Molecular Biology Article Neutrophil Activation chemistry.chemical_compound Allosteric Regulation Phagocytosis Humans Glycolysis Phosphofructokinase-1 Liver Type Protein Kinase Inhibitors Respiratory Burst chemistry.chemical_classification Reactive oxygen species Phagocytes Microbial Viability NADPH oxidase biology Intracellular Signaling Peptides and Proteins NADPH Oxidases Epithelial Cells Phosphate-Binding Proteins Adenosine Monophosphate Recombinant Proteins Cell biology Respiratory burst Adenosine Diphosphate Enzyme Activation Kinetics Glucose chemistry PFKM PFKP biology.protein Tetradecanoylphorbol Acetate Nicotinamide adenine dinucleotide phosphate |
| Zdroj: | Cell |
| ISSN: | 1097-4172 0092-8674 |
| Popis: | SUMMARY In neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) generated via the pentose phosphate pathway fuels NADPH oxidase NOX2 to produce reactive oxygen species for killing invading pathogens. However, excessive NOX2 activity can exacerbate inflammation, as in acute respiratory distress syndrome (ARDS). Here, we use two unbiased chemical proteomic strategies to show that small-molecule LDC7559, or a more potent designed analog NA-11, inhibits the NOX2-dependent oxidative burst in neutrophils by activating the glycolytic enzyme phosphofructokinase-1 liver type (PFKL) and dampening flux through the pentose phosphate pathway. Accordingly, neutrophils treated with NA-11 had reduced NOX2-dependent outputs, including neutrophil cell death (NETosis) and tissue damage. A high-resolution structure of PFKL confirmed binding of NA-11 to the AMP/ADP allosteric activation site and explained why NA-11 failed to agonize phosphofructokinase-1 platelet type (PFKP) or muscle type (PFKM). Thus, NA-11 represents a tool for selective activation of PFKL, the main phosphofructokinase-1 isoform expressed in immune cells. Graphical Abstract In brief The small molecule LDC7559 and its more potent analog, NA-11, suppress excessive NOX2-dependent oxidative burst and NETosis, as well as subsequent tissue damage and inflammation, without compromising basal ROS production. They selectively activate the glycolytic enzyme phosphofructokinase-1 liver type (PFKL) to suppress glycolytic flux through the pentose phosphate pathway that leads to NOX2-dependent outputs. |
| Databáze: | OpenAIRE |
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