The physicochemical properties of membranes correlate with the NADPH oxidase activity

Souabni, Hager; Wien, Frank; Bizouarn, Tania; Houée-Levin⊥, Chantal; Réfrégiers, Matthieu; Baciou, Laura

doi:10.1016/j.bbagen.2016.06.028

Cited by 12 publications

(3 citation statements)

References 61 publications

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“…Increases in core body temperature are well established to promote neutrophil accumulation, NADPH oxidase activity, and production rates of toxic superoxide anions. 45 Models of fever-range hyperthermia (FRH) have linked these effects to higher serum concentrations of IL-1, TNF, and IL-6, 46, 47 G-CSF-driven release of neutrophils from the hematopoietic bone marrow, 48, 49 expansion of the circulating neutrophil pool, 48, 49 increased endothelial barrier permeability in blood vessels, 50 and upregulation of GM-CSF, extracellular HSP70, IL-8 and other CXC chemokines at the local site of infection. 51, 52 However, these thermal increases have also been shown to promote collateral tissue injury.…”

Section: Discussionmentioning

confidence: 99%

A cold-blooded vertebrate shows integration of antimicrobial defenses and tissue repair through fever

Haddad

Soliman

Wong

et al. 2022

Preprint

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Multiple lines of evidence support the value of moderate fever to host survival, but the mechanisms involved remain unclear. This is difficult to establish in warm-blooded animal models, given the strict programs controlling core body temperature and the physiological stress that results from their disruption. Thus, we took advantage of a cold-blooded teleost fish that offered natural kinetics for the induction and regulation of fever and a broad range of tolerated temperatures. A custom swim chamber, coupled to high-fidelity quantitative positional tracking, showed remarkable consistency in fish behaviours and defined the febrile window. Animals exerting fever engaged pyrogenic cytokine gene programs in the CNS, increased efficiency of leukocyte recruitment into the immune challenge site, and markedly improved pathogen clearancein vivo, even when an infecting bacterium grew better at higher temperatures. Contrary to earlier speculations for global upregulation of immunity, we identified selectivity in the protective immune mechanisms activated through fever. Fever then inhibited inflammation and markedly improved wound repair. Artificial mechanical hyperthermia, often used as a model of fever, recapitulated some but not all benefits achieved through natural host-driven dynamic thermoregulation. Together, our results define fever as an integrative host response that regulates induction and resolution of acute inflammation, and demonstrate that this integrative strategy emerged prior to endothermy during evolution.

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Section: Discussionmentioning

confidence: 99%

A cold-blooded vertebrate shows integration of antimicrobial defenses and tissue repair through fever

Haddad

Soliman

Wong

et al. 2022

Preprint

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“…The importance of the lipid metabolism was evidenced in NOX activities, although the regulatory role of the lipid membrane properties remains unclear. Membrane properties (charges, thickness, composition, lipid raft formation) have been shown to affect the NOX2 enzyme functioning (Shao et al, 2003 ; Souabni et al, 2014 , 2017 ). Moreover, the phospholipid composition changes during NOX2 activation (Magalhaes and Glogauer, 2010 ; Bréchard et al, 2012 ; Joly et al, 2020 ).…”

Section: Building Of An Atomistic Model For Nox5mentioning

confidence: 99%

Mechanistic Insights on Heme-to-Heme Transmembrane Electron Transfer Within NADPH Oxydases From Atomistic Simulations

Hénin

Baciou

et al. 2021

Front. Chem.

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NOX5 is a member of the NADPH oxidase family which is dedicated to the production of reactive oxygen species. The molecular mechanisms governing transmembrane electron transfer (ET) that permits to shuttle electrons over the biological membrane have remained elusive for a long time. Using computer simulations, we report conformational dynamics of NOX5 embedded within a realistic membrane environment. We assess the stability of the protein within the membrane and monitor the existence of cavities that could accommodate dioxygen molecules. We investigate the heme-to-heme electron transfer. We find a reaction free energy of a few tenths of eV (ca. −0.3 eV) and a reorganization free energy of around 1.1 eV (0.8 eV after including electrostatic induction corrections). The former indicates thermodynamically favorable ET, while the latter falls in the expected values for transmembrane inter-heme ET. We estimate the electronic coupling to fall in the range of the μeV. We identify electron tunneling pathways showing that not only the W378 residue is playing a central role, but also F348. Finally, we reveal the existence of two connected O2−binding pockets near the outer heme with fast exchange between the two sites on the nanosecond timescale. We show that when the terminal heme is reduced, O2 binds closer to it, affording a more efficient tunneling pathway than when the terminal heme is oxidized, thereby providing an efficient mechanism to catalyze superoxide production in the final step. Overall, our study reveals some key molecular mechanisms permitting reactive oxygen species production by NOX5 and paves the road for further investigation of ET processes in the wide family of NADPH oxidases by computer simulations.

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“…Nevertheless, this structural information is based only on fragments (peptide) or domains of these proteins. In addition, many other studies were performed to unravel the complex assembly, some of them implying the crucial role of the surrounding membrane, including specific lipids (12)(13)(14) (15,16) or the PX domain of p47 phox and the PB region of Rac described as being essential to the complex assembly. All this information was used to propose a scenario for assembling the complex but the overall structure of the active complex, and the structural changes required of the various protein partners to form it remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Combining computational biology and experimental knowledge to draw a structural profile of the active membrane-assembled NADPH oxidase complex

Aimeur,

Fas,

Serfaty

et al. 2024

Preprint

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The phagocyte NADPH oxidase complex (NOX2) is activated by various intracellular stimuli, resulting in the generation of reactive oxygen species, which are responsible for many physiological processes, including innate immune defense. Structures of the cytochrome b558, membrane catalytic core of the complex, in their resting state have been solved experimentally. Unfortunately, very little is known about the structure of the active complex, as it involves the assembly of modular proteins and disordered regions, that have been shown to be essential to the function of the enzyme. Here, we modelled the supra-structure of the active complex using Alphafold2 and taking into account experimental data as well as conformational analyses by SRCD. AF2 ability to generate complexes enabled us to visualize ways in which subunits could assemble together, and revealed the implications of intrinsically disordered regions in protein-protein and membrane-protein interactions. Additional Molecular Dynamics simulations of the membrane embedded complex bring further insight regarding the system dynamics. Altogether, our work provides evidence for a model of the structure of the active complex where disordered regions can enable multi-subunit assembly.

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The physicochemical properties of membranes correlate with the NADPH oxidase activity

Cited by 12 publications

References 61 publications

A cold-blooded vertebrate shows integration of antimicrobial defenses and tissue repair through fever

A cold-blooded vertebrate shows integration of antimicrobial defenses and tissue repair through fever

Mechanistic Insights on Heme-to-Heme Transmembrane Electron Transfer Within NADPH Oxydases From Atomistic Simulations

Combining computational biology and experimental knowledge to draw a structural profile of the active membrane-assembled NADPH oxidase complex

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