Selective activation of PFKL suppresses the phagocytic oxidative burst.
Adenosine Diphosphate
/ metabolism
Adenosine Monophosphate
/ metabolism
Allosteric Regulation
/ drug effects
Enzyme Activation
/ drug effects
Epithelial Cells
/ drug effects
Glycolysis
/ drug effects
Humans
Intracellular Signaling Peptides and Proteins
/ metabolism
Kinetics
Microbial Viability
/ drug effects
Models, Molecular
NADPH Oxidases
/ metabolism
Neutrophils
/ drug effects
Phagocytosis
/ drug effects
Phosphate-Binding Proteins
/ metabolism
Phosphofructokinase-1, Liver Type
/ antagonists & inhibitors
Protein Kinase Inhibitors
/ chemistry
Recombinant Proteins
/ isolation & purification
Respiratory Burst
/ drug effects
Tetradecanoylphorbol Acetate
/ pharmacology
LDC7559
NA-11
NADPH
NETosis
NOX2
PFKL
ROS
neutrophils
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
19 08 2021
19 08 2021
Historique:
received:
10
03
2021
revised:
20
05
2021
accepted:
01
07
2021
pubmed:
29
7
2021
medline:
6
1
2022
entrez:
28
7
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34320407
pii: S0092-8674(21)00830-8
doi: 10.1016/j.cell.2021.07.004
pmc: PMC8802628
mid: NIHMS1770610
pii:
doi:
Substances chimiques
GSDMD protein, human
0
Intracellular Signaling Peptides and Proteins
0
Phosphate-Binding Proteins
0
Protein Kinase Inhibitors
0
Recombinant Proteins
0
Adenosine Monophosphate
415SHH325A
Adenosine Diphosphate
61D2G4IYVH
NADPH Oxidases
EC 1.6.3.-
Phosphofructokinase-1, Liver Type
EC 2.7.1.-
Tetradecanoylphorbol Acetate
NI40JAQ945
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4480-4494.e15Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM118396
Pays : United States
Organisme : NIH HHS
ID : S10 OD023476
Pays : United States
Organisme : NIGMS NIH HHS
ID : U54 GM104942
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 Genentech Inc. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests N.A., T.M., K.Y., Z.L., D.S., N.K., K.N., S.T.S., and V.M.D. are employees of Genentech.
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