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Article ; Online: Cell death.

Newton, Kim / Strasser, Andreas / Kayagaki, Nobuhiko / Dixit, Vishva M

2024 Volume 187, Issue 2, Page(s) 235–256

Abstract: Cell death supports morphogenesis during development and homeostasis after birth by removing damaged or obsolete cells. It also curtails the spread of pathogens by eliminating infected cells. Cell death can be induced by the genetically programmed ... ...

Abstract	Cell death supports morphogenesis during development and homeostasis after birth by removing damaged or obsolete cells. It also curtails the spread of pathogens by eliminating infected cells. Cell death can be induced by the genetically programmed suicide mechanisms of apoptosis, necroptosis, and pyroptosis, or it can be a consequence of dysregulated metabolism, as in ferroptosis. Here, we review the signaling mechanisms underlying each cell-death pathway, discuss how impaired or excessive activation of the distinct cell-death processes can promote disease, and highlight existing and potential therapies for redressing imbalances in cell death in cancer and other diseases.
MeSH term(s)	Humans ; Apoptosis ; Cell Death ; Ferroptosis ; Homeostasis ; Pyroptosis ; Signal Transduction
Language	English
Publishing date	2024-01-06
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2023.11.044
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Article ; Online: Control of Cell Death in Health and Disease.

Kayagaki, Nobuhiko / Webster, Joshua D / Newton, Kim

Annual review of pathology

2023 Volume 19, Page(s) 157–180

Abstract: Apoptosis, necroptosis, and pyroptosis are genetically programmed cell death mechanisms that eliminate obsolete, damaged, infected, and self-reactive cells. Apoptosis fragments cells in a manner that limits immune cell activation, whereas the lytic death ...

Abstract	Apoptosis, necroptosis, and pyroptosis are genetically programmed cell death mechanisms that eliminate obsolete, damaged, infected, and self-reactive cells. Apoptosis fragments cells in a manner that limits immune cell activation, whereas the lytic death programs of necroptosis and pyroptosis release proinflammatory intracellular contents. Apoptosis fine-tunes tissue architecture during mammalian development, promotes tissue homeostasis, and is crucial for averting cancer and autoimmunity. All three cell death mechanisms are deployed to thwart the spread of pathogens. Disabling regulators of cell death signaling in mice has revealed how excessive cell death can fuel acute or chronic inflammation. Here we review strategies for modulating cell death in the context of disease. For example, BCL-2 inhibitor venetoclax, an inducer of apoptosis, is approved for the treatment of certain hematologic malignancies. By contrast, inhibition of RIPK1, NLRP3, GSDMD, or NINJ1 to limit proinflammatory cell death and/or the release of large proinflammatory molecules from dying cells may benefit patients with inflammatory diseases.
MeSH term(s)	Humans ; Animals ; Mice ; Cell Death ; Apoptosis ; Autoimmunity ; Inflammation ; Mammals ; Nerve Growth Factors ; Cell Adhesion Molecules, Neuronal
Chemical Substances	NINJ1 protein, human ; Nerve Growth Factors ; Cell Adhesion Molecules, Neuronal
Language	English
Publishing date	2023-10-03
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2227429-7
ISSN	1553-4014 ; 1553-4006
ISSN (online)	1553-4014
ISSN	1553-4006
DOI	10.1146/annurev-pathmechdis-051022-014433
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Article ; Online: Epigenetic and transcriptional control of gasdermins.

Cadena, Cristhian / Kornfeld, Opher S / Lee, Bettina L / Kayagaki, Nobuhiko

Seminars in immunology

2023 Volume 70, Page(s) 101841

Abstract: Cells undergo an inflammatory programmed lytic cell death called 'pyroptosis' (with the Greek roots 'fiery'), often featuring morphological hallmarks such as large ballooning protrusions and subsequent bursting. Originally described as a caspase-1- ... ...

Abstract	Cells undergo an inflammatory programmed lytic cell death called 'pyroptosis' (with the Greek roots 'fiery'), often featuring morphological hallmarks such as large ballooning protrusions and subsequent bursting. Originally described as a caspase-1-dependent cell death in response to bacterial infection, pyroptosis has since been re-defined in 2018 as a cell death dependent on plasma membrane pores by a gasdermin (GSDM) family member [1,2]. GSDMs form pores in the plasma membrane as well as organelle membranes, thereby initiating membrane destruction and the rapid and lytic demise of a cell. The gasdermin family plays a profound role in the execution of pyroptosis in the context of infection, inflammation, tumor pathogenesis, and anti-tumor therapy. More recently, cell-death-independent functions for some of the GSDMs have been proposed. Therefore, a comprehensive understanding of gasdermin gene regulation, including mechanisms in both homeostatic conditions and during inflammation, is essential. In this review, we will summarize the role of gasdermins in pyroptosis and focus our discussion on the transcriptional and epigenetic mechanisms controlling the expression of GSDMs.
MeSH term(s)	Humans ; Gasdermins ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Apoptosis ; Inflammation/metabolism ; Epigenesis, Genetic ; Inflammasomes/metabolism
Chemical Substances	Gasdermins ; Neoplasm Proteins ; Inflammasomes
Language	English
Publishing date	2023-09-11
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1018141-6
ISSN	1096-3618 ; 1044-5323
ISSN (online)	1096-3618
ISSN	1044-5323
DOI	10.1016/j.smim.2023.101841
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Article ; Online: Dying cells fan the flames of inflammation.

Newton, Kim / Dixit, Vishva M / Kayagaki, Nobuhiko

Science (New York, N.Y.)

2021 Volume 374, Issue 6571, Page(s) 1076–1080

Abstract: Inflammatory processes that recruit leukocytes to injured or infected tissues are crucial for tissue repair and the elimination of pathogens. However, excessive or chronic inflammation promotes tissue damage and disease, as in arthritis, atherosclerosis, ...

Abstract	Inflammatory processes that recruit leukocytes to injured or infected tissues are crucial for tissue repair and the elimination of pathogens. However, excessive or chronic inflammation promotes tissue damage and disease, as in arthritis, atherosclerosis, inflammatory bowel disease, and COVID-19. Intracellular constituents released from dying cells are among the stimuli that trigger proinflammatory gene expression programs in innate immune cells. We explore how programmed cell death mechanisms—apoptosis, necroptosis, and pyroptosis—may contribute to inflammatory disease. We discuss inhibition of cell death as a potential therapeutic strategy, focusing on the targets RIPK1 (receptor interacting serine/threonine kinase 1), NLRP3 (NLR family pyrin domain containing 3), and GSDMD (gasdermin D) as important mediators of lytic cell death. We also consider the potential benefits of limiting membrane rupture rather than cell death by targeting NINJ1.
MeSH term(s)	Animals ; Apoptosis ; Caspase 8/metabolism ; Cell Adhesion Molecules, Neuronal/antagonists & inhibitors ; Cell Adhesion Molecules, Neuronal/metabolism ; Fas-Associated Death Domain Protein/metabolism ; Humans ; Inflammasomes/metabolism ; Inflammation/drug therapy ; Inflammation/physiopathology ; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Necroptosis ; Nerve Growth Factors/antagonists & inhibitors ; Nerve Growth Factors/metabolism ; Pyroptosis ; Receptor-Interacting Protein Serine-Threonine Kinases/deficiency ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
Chemical Substances	Cell Adhesion Molecules, Neuronal ; Fas-Associated Death Domain Protein ; Inflammasomes ; Intracellular Signaling Peptides and Proteins ; NINJ1 protein, human ; NLR Family, Pyrin Domain-Containing 3 Protein ; Nerve Growth Factors ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Caspase 8 (EC 3.4.22.-)
Language	English
Publishing date	2021-11-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.abi5934
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Article ; Online: Rescue from a fiery death: A therapeutic endeavor.

Kayagaki, Nobuhiko / Dixit, Vishva M

Science (New York, N.Y.)

2019 Volume 366, Issue 6466, Page(s) 688–689

MeSH term(s)	Animals ; Caspase 1/metabolism ; Caspase 2/metabolism ; Cytokines/metabolism ; Humans ; Inflammasomes/metabolism ; Inflammation/immunology ; Inflammation/pathology ; Intracellular Signaling Peptides and Proteins/metabolism ; Mice ; Neoplasms/immunology ; Neoplasms/pathology ; Phosphate-Binding Proteins/metabolism ; Pyroptosis
Chemical Substances	Cytokines ; GSDMD protein, human ; Inflammasomes ; Intracellular Signaling Peptides and Proteins ; Phosphate-Binding Proteins ; Caspase 2 (EC 3.4.22.-) ; Caspase 1 (EC 3.4.22.36)
Language	English
Publishing date	2019-11-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.aaw1177
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Article ; Online: Caspase-11: arming the guards against bacterial infection.

Stowe, Irma / Lee, Bettina / Kayagaki, Nobuhiko

Immunological reviews

2015 Volume 265, Issue 1, Page(s) 75–84

Abstract: As a front line of defense against pathogenic microbes, our body employs a primitive, yet highly sophisticated and potent innate immune response pathway collectively referred to as the inflammasome. Innate immune cells, epithelial cells, and many other ... ...

Abstract	As a front line of defense against pathogenic microbes, our body employs a primitive, yet highly sophisticated and potent innate immune response pathway collectively referred to as the inflammasome. Innate immune cells, epithelial cells, and many other cell types are capable of detecting infection or tissue injury and mounting a coordinated molecular defense. For example, Gram-negative bacteria are specifically detected via a surveillance mechanism that involves activation of extracellular receptors such as Toll-like receptors (TLRs) followed by intracellular recognition and activation of pathways such as caspase-11 (caspase-4/5 in humans). Importantly, lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria, is a strong trigger of these pathways. Extracellular LPS primarily stimulates TLR4, which can serve as a priming signal for expression of inflammasome components. Intracellular LPS can then trigger caspase-11-dependent inflammasome activation in the cytoplasm. Here, we briefly review the burgeoning caspase-11-dependent non-canonical inflammasome field, focusing mainly on the innate sensing of LPS.
MeSH term(s)	Animals ; Bacterial Infections/immunology ; Bacterial Infections/metabolism ; Caspases/immunology ; Caspases/metabolism ; Caspases, Initiator/immunology ; Caspases, Initiator/metabolism ; Humans ; Immunity, Innate ; Lipopolysaccharides/immunology ; Mice ; Multiprotein Complexes/immunology ; Multiprotein Complexes/metabolism ; Signal Transduction ; Toll-Like Receptor 4/metabolism
Chemical Substances	Lipopolysaccharides ; Multiprotein Complexes ; Toll-Like Receptor 4 ; CASP4 protein, human (EC 3.4.22.-) ; Casp11 protein, mouse (EC 3.4.22.-) ; Caspases (EC 3.4.22.-) ; Caspases, Initiator (EC 3.4.22.-)
Language	English
Publishing date	2015-05
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	391796-4
ISSN	1600-065X ; 0105-2896
ISSN (online)	1600-065X
ISSN	0105-2896
DOI	10.1111/imr.12292
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Article: Selective activation of PFKL suppresses the phagocytic oxidative burst

Amara, Neri / Cooper, Madison P. / Voronkova, Maria A. / Webb, Bradley A. / Lynch, Eric M. / Kollman, Justin M. / Ma, Taylur / Yu, Kebing / Lai, Zijuan / Sangaraju, Dewakar / Kayagaki, Nobuhiko / Newton, Kim / Bogyo, Matthew / Staben, Steven T. / Dixit, Vishva M.

Cell. 2021 Aug. 19, v. 184, no. 17

2021

Abstract: 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 ... ...

Abstract	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.
Keywords	6-phosphofructokinase ; NAD(P)H oxidase (H2O2-forming) ; NADP (coenzyme) ; acute respiratory distress syndrome ; cell death ; glycolysis ; inflammation ; liver ; muscles ; neutrophils ; pentose phosphate cycle ; proteomics ; reactive oxygen species
Language	English
Dates of publication	2021-0819
Size	p. 4480-4494.e15.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2021.07.004
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Article ; Online: Discovery of a caspase cleavage motif antibody reveals insights into noncanonical inflammasome function.

Davies, Christopher W / Stowe, Irma / Phung, Qui T / Ho, Hoangdung / Bakalarski, Corey E / Gupta, Aaron / Zhang, Yingnan / Lill, Jennie R / Payandeh, Jian / Kayagaki, Nobuhiko / Koerber, James T

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 12

Abstract: Inflammasomes sense a number of pathogen and host damage signals to initiate a signaling cascade that triggers inflammatory cell death, termed pyroptosis. The inflammatory caspases (1/4/5/11) are the key effectors of this process through cleavage and ... ...

Abstract	Inflammasomes sense a number of pathogen and host damage signals to initiate a signaling cascade that triggers inflammatory cell death, termed pyroptosis. The inflammatory caspases (1/4/5/11) are the key effectors of this process through cleavage and activation of the pore-forming protein gasdermin D. Caspase-1 also activates proinflammatory interleukins, IL-1β and IL-18, via proteolysis. However, compared to the well-studied apoptotic caspases, the identity of substrates and therefore biological functions of the inflammatory caspases remain limited. Here, we construct, validate, and apply an antibody toolset for direct detection of neo-C termini generated by inflammatory caspase proteolysis. By combining rabbit immune phage display with a set of degenerate and defined target peptides, we discovered two monoclonal antibodies that bind peptides with a similar degenerate recognition motif as the inflammatory caspases without recognizing the canonical apoptotic caspase recognition motif. Crystal structure analyses revealed the molecular basis of this strong yet paradoxical degenerate mode of peptide recognition. One antibody selectively immunoprecipitated cleaved forms of known and unknown inflammatory caspase substrates, allowing the identification of over 300 putative substrates of the caspase-4 noncanonical inflammasome, including caspase-7. This dataset will provide a path toward developing blood-based biomarkers of inflammasome activation. Overall, our study establishes tools to discover and detect inflammatory caspase substrates and functions, provides a workflow for designing antibody reagents to study cell signaling, and extends the growing evidence of biological cross talk between the apoptotic and inflammatory caspases.
MeSH term(s)	Amino Acid Motifs ; Amino Acid Sequence ; Antibodies/chemistry ; Antibodies/metabolism ; Binding Sites ; Caspases/chemistry ; Caspases/metabolism ; Inflammasomes/metabolism ; Models, Molecular ; Peptides/chemistry ; Peptides/metabolism ; Protein Binding ; Protein Interaction Domains and Motifs ; Proteolysis ; Signal Transduction ; Structure-Activity Relationship
Chemical Substances	Antibodies ; Inflammasomes ; Peptides ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2021-03-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2018024118
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Article ; Online: Evolutionary loss of inflammasomes in the Carnivora and implications for the carriage of zoonotic infections.

Digby, Zsofi / Tourlomousis, Panagiotis / Rooney, James / Boyle, Joseph P / Bibo-Verdugo, Betsaida / Pickering, Robert J / Webster, Steven J / Monie, Thomas P / Hopkins, Lee J / Kayagaki, Nobuhiko / Salvesen, Guy S / Warming, Soren / Weinert, Lucy / Bryant, Clare E

Cell reports

2021 Volume 36, Issue 8, Page(s) 109614

Abstract: Zoonotic pathogens, such as COVID-19, reside in animal hosts before jumping species to infect humans. The Carnivora, like mink, carry many zoonoses, yet how diversity in host immune genes across species affect pathogen carriage is poorly understood. Here, ...

Abstract	Zoonotic pathogens, such as COVID-19, reside in animal hosts before jumping species to infect humans. The Carnivora, like mink, carry many zoonoses, yet how diversity in host immune genes across species affect pathogen carriage is poorly understood. Here, we describe a progressive evolutionary downregulation of pathogen-sensing inflammasome pathways in Carnivora. This includes the loss of nucleotide-oligomerization domain leucine-rich repeat receptors (NLRs), acquisition of a unique caspase-1/-4 effector fusion protein that processes gasdermin D pore formation without inducing rapid lytic cell death, and the formation of a caspase-8 containing inflammasome that inefficiently processes interleukin-1β. Inflammasomes regulate gut immunity, but the carnivorous diet has antimicrobial properties that could compensate for the loss of these immune pathways. We speculate that the consequences of systemic inflammasome downregulation, however, can impair host sensing of specific pathogens such that they can reside undetected in the Carnivora.
MeSH term(s)	Animals ; Carnivora/metabolism ; Caspase 1/genetics ; Caspase 1/metabolism ; Caspase 8/metabolism ; Caspases, Initiator/genetics ; Caspases, Initiator/metabolism ; Cell Death ; Cell Line ; Evolution, Molecular ; Humans ; Inflammasomes/metabolism ; Interleukin-1beta/metabolism ; Lipopolysaccharides/pharmacology ; Macrophages/cytology ; Macrophages/drug effects ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; NLR Proteins/genetics ; NLR Proteins/metabolism ; Recombinant Fusion Proteins/biosynthesis ; Recombinant Fusion Proteins/genetics ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Salmonella typhi/pathogenicity ; Zoonoses/immunology ; Zoonoses/parasitology ; Zoonoses/pathology
Chemical Substances	Inflammasomes ; Interleukin-1beta ; Lipopolysaccharides ; NLR Proteins ; Recombinant Fusion Proteins ; Recombinant Proteins ; Caspase 8 (EC 3.4.22.-) ; Caspases, Initiator (EC 3.4.22.-) ; Caspase 1 (EC 3.4.22.36)
Language	English
Publishing date	2021-08-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2021.109614
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Article ; Online: Selective activation of PFKL suppresses the phagocytic oxidative burst.

Amara, Neri / Cooper, Madison P / Voronkova, Maria A / Webb, Bradley A / Lynch, Eric M / Kollman, Justin M / Ma, Taylur / Yu, Kebing / Lai, Zijuan / Sangaraju, Dewakar / Kayagaki, Nobuhiko / Newton, Kim / Bogyo, Matthew / Staben, Steven T / Dixit, Vishva M

Cell

2021 Volume 184, Issue 17, Page(s) 4480–4494.e15

Abstract	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.
MeSH term(s)	Adenosine Diphosphate/metabolism ; Adenosine Monophosphate/metabolism ; Allosteric Regulation/drug effects ; Enzyme Activation/drug effects ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Glycolysis/drug effects ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Kinetics ; Microbial Viability/drug effects ; Models, Molecular ; NADPH Oxidases/metabolism ; Neutrophils/drug effects ; Neutrophils/metabolism ; Phagocytosis/drug effects ; Phosphate-Binding Proteins/metabolism ; Phosphofructokinase-1, Liver Type/antagonists & inhibitors ; Phosphofructokinase-1, Liver Type/metabolism ; Phosphofructokinase-1, Liver Type/ultrastructure ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Recombinant Proteins/isolation & purification ; Respiratory Burst/drug effects ; Tetradecanoylphorbol Acetate/pharmacology
Chemical Substances	GSDMD protein, human ; Intracellular Signaling Peptides and Proteins ; Phosphate-Binding Proteins ; Protein Kinase Inhibitors ; Recombinant Proteins ; Adenosine Monophosphate (415SHH325A) ; Adenosine Diphosphate (61D2G4IYVH) ; NADPH Oxidases (EC 1.6.3.-) ; Phosphofructokinase-1, Liver Type (EC 2.7.1.-) ; Tetradecanoylphorbol Acetate (NI40JAQ945)
Language	English
Publishing date	2021-07-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2021.07.004
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