The phagocyte NOX2 NADPH oxidase in microbial killing and cell signaling

Nauseef, William M.

doi:10.1016/j.coi.2019.05.006

Cited by 122 publications

(102 citation statements)

References 83 publications

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“…The innate immune response against microbial, fungal, and protozoal pathogens comprises, as a major effector mechanism, the production by phagocytic cells of reactive oxygen species (ROS) . These originate from the superoxide anion (O 2 .− ), generated by the NADPH‐derived one‐electron reduction of molecular oxygen (O 2 ).…”

Section: Introductionmentioning

confidence: 99%

p67phox binds to a newly identified site in Nox2 following the disengagement of an intramolecular bond—Canaan sighted?

Bechor

Zahavi

Amichay

et al. 2020

Journal of Leukocyte Biology

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Activation of the phagocyte NADPH oxidase involves a conformational change in Nox2. The effector in this process is p67phox and there is evidence for a change in the configuration of p67phox being required for binding to Nox2. To study this, we measured binding of p67phox to a library of Nox2 peptides and binding of NusA–Nox2 fusion proteins to p67phox. We found, serendipitously, that deletion of residues 259–279 in p67phox (p67phoxΔ(259–279)), endowed it with the ability to bind selectively to Nox2 peptide 369–383 (peptide 28). There was no binding to scrambled Nox2 peptide 28 and to Nox4 peptide 28. Binding was cysteine independent and resistant to reducing and alkylating agents. Truncations of peptide 28 revealed that the actual binding site consisted of residues 375–383. Binding of p67phoxΔ(259–279) to peptide 28 was mimicked by that of a (p67phox‐RacGTP) chimera. Both p67phoxΔ(259–279) and the (p67pho–RacGTP) chimera bound a NusA–Nox2 fusion protein, comprising residues 375–383. Specific single residue deletion mutants, within the p67phox sequence 259–279, were also bound to Nox2 peptide 28. Peptides synthesized to correspond to the 259–279 sequence in p67phox, were found to autobind p67phox, suggesting that an intramolecular bond exists in p67phox, one pole of which was located within residues 259–279. We conclude that “resting” p67phox exists in a “closed” conformation, generated by an intramolecular bond. Deletion of specific residues within the 259–279 sequence, in vitro, or interaction with RacGTP, in vivo, causes “opening” of the bond and results in binding of p67phox to a specific, previously unknown, site in Nox2.

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Section: Introductionmentioning

confidence: 99%

p67phox binds to a newly identified site in Nox2 following the disengagement of an intramolecular bond—Canaan sighted?

Bechor

Zahavi

Amichay

et al. 2020

Journal of Leukocyte Biology

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“…In contrast to the transcriptional neutrophil profile elicited by A. phagocytophilum, our RNAseq and qPCR results indicate a significant downregulation of the gene that encodes for one of the cytosolic components of the NADPH oxidase, p47phox, and a significant time-dependent increase in the gene expression of galectin 3 ( Figures 1E,F and Table 3). P47phox, together with p67phox and p40phox, form the triad cytoplasmic complex, in a 1:1:1 stoichiometric ratio, which is essential for NADPH oxidase activation (61). Although the minimal ROS induced by F. alocischallenged neutrophils was monitored between 1 and 90 min and the significant decrease in p47phox gene expression was observed at 6 h post-infection, these pathogen-induced changes in the transcript levels could leave neutrophils defective in mounting an appropriate respiratory burst response.…”

Section: Discussionmentioning

confidence: 99%

“…To mount an efficacious antimicrobial response inside the neutrophil phagosome, the synergy between an optimal activation of the NADPH oxidase and the fusion of the different neutrophil granule subtypes with the bacteria-containing phagosome is essential (61). Microbial pathogens manipulate either one or both of these antimicrobial processes to evade neutrophil killing (62).…”

Section: Discussionmentioning

confidence: 99%

Whole Transcriptome Analysis Reveals That Filifactor alocis Modulates TNFα-Stimulated MAPK Activation in Human Neutrophils

et al. 2020

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“…Upon formation, the superoxide anion will then transform into further ROIs such as hydrogen peroxide, hydroxyl radical, and hypochlorous acid, all of which efficiently kill the phagocytosed microorganisms [ 82 ]. Inactive NOX consists of six subunits wherein gp91 phox and p22 phox are membrane proteins ( Figure 1 A) that together are known as flavocytochrome b 558 (cyt b 558 , [ 83 ]). The remaining four regulatory subunits, (p40 phox , p47 phox , p67 phox and Rac2) normally exist in the cytosol ( Figure 1 A) but upon the activation of leukocytes by particulate stimuli, will translocate to the membrane and associate with cyt b 558 ( Figure 1 B) to form the active oxidase (reviewed in [ 80 , 83 ]).…”

Section: Teleostean Immunity: Our Current Understanding Of the Antmentioning

confidence: 99%

“…Inactive NOX consists of six subunits wherein gp91 phox and p22 phox are membrane proteins ( Figure 1 A) that together are known as flavocytochrome b 558 (cyt b 558 , [ 83 ]). The remaining four regulatory subunits, (p40 phox , p47 phox , p67 phox and Rac2) normally exist in the cytosol ( Figure 1 A) but upon the activation of leukocytes by particulate stimuli, will translocate to the membrane and associate with cyt b 558 ( Figure 1 B) to form the active oxidase (reviewed in [ 80 , 83 ]). It is well established that fish phagocytes possess all of these NADPH oxidase components as well as an RBA response comparable to that of mammals [ 84 , 85 , 86 ].…”

Section: Teleostean Immunity: Our Current Understanding Of the Antmentioning

confidence: 99%

Salmonid Antibacterial Immunity: An Aquaculture Perspective

Semple

Dixon

2020

Biology

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The aquaculture industry is continuously threatened by infectious diseases, including those of bacterial origin. Regardless of the disease burden, aquaculture is already the main method for producing fish protein, having displaced capture fisheries. One attractive sector within this industry is the culture of salmonids, which are (a) uniquely under pressure due to overfishing and (b) the most valuable finfish per unit of weight. There are still knowledge gaps in the understanding of fish immunity, leading to vaccines that are not as effective as in terrestrial species, thus a common method to combat bacterial disease outbreaks is the use of antibiotics. Though effective, this method increases both the prevalence and risk of generating antibiotic-resistant bacteria. To facilitate vaccine design and/or alternative treatment efforts, a deeper understanding of the teleost immune system is essential. This review highlights the current state of teleost antibacterial immunity in the context of salmonid aquaculture. Additionally, the success of current techniques/methods used to combat bacterial diseases in salmonid aquaculture will be addressed. Filling the immunology knowledge gaps highlighted here will assist in reducing aquaculture losses in the future.

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The phagocyte NOX2 NADPH oxidase in microbial killing and cell signaling

Cited by 122 publications

References 83 publications

p67phox binds to a newly identified site in Nox2 following the disengagement of an intramolecular bond—Canaan sighted?

p67phox binds to a newly identified site in Nox2 following the disengagement of an intramolecular bond—Canaan sighted?

Whole Transcriptome Analysis Reveals That Filifactor alocis Modulates TNFα-Stimulated MAPK Activation in Human Neutrophils

Salmonid Antibacterial Immunity: An Aquaculture Perspective

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