Enzymatic regulation and functional relevance of NOX5

Chen, Feng; Wang, Yusi; Barman, Scott A.; Fulton, David

doi:10.2174/1381612821666151029111528

Cited by 29 publications

(28 citation statements)

References 71 publications

(139 reference statements)

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“…NOX4 is constitutively active in the presence of p22- phox [26] simply because the conformation of its DH domain seems to allow the transfer of electrons from NADPH to FAD [27]. In the other two subfamilies, NOX5 and DUOX1-2, apart from other proteins, calcium molecules are important for ROS production since they are needed for enzyme activation [10, 15, 28–31]. …”

Section: Introductionmentioning

confidence: 99%

Evolutionary origin and function of NOX4-art, an arthropod specific NADPH oxidase

et al. 2017

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BackgroundNADPH oxidases (NOX) are ROS producing enzymes that perform essential roles in cell physiology, including cell signaling and antimicrobial defense. This gene family is present in most eukaryotes, suggesting a common ancestor. To date, only a limited number of phylogenetic studies of metazoan NOXes have been performed, with few arthropod genes. In arthropods, only NOX5 and DUOX genes have been found and a gene called NOXm was found in mosquitoes but its origin and function has not been examined. In this study, we analyzed the evolution of this gene family in arthropods. A thorough search of genomes and transcriptomes was performed enabling us to browse most branches of arthropod phylogeny.ResultsWe have found that the subfamilies NOX5 and DUOX are present in all arthropod groups. We also show that a NOX gene, closely related to NOX4 and previously found only in mosquitoes (NOXm), can also be found in other taxonomic groups, leading us to rename it as NOX4-art. Although the accessory protein p22-phox, essential for NOX1-4 activation, was not found in any of the arthropods studied, NOX4-art of Aedes aegypti encodes an active protein that produces H2O2. Although NOX4-art has been lost in a number of arthropod lineages, it has all the domains and many signature residues and motifs necessary for ROS production and, when silenced, H2O2 production is considerably diminished in A. aegypti cells.ConclusionsCombining all bioinformatic analyses and laboratory work we have reached interesting conclusions regarding arthropod NOX gene family evolution. NOX5 and DUOX are present in all arthropod lineages but it seems that a NOX2-like gene was lost in the ancestral lineage leading to Ecdysozoa. The NOX4-art gene originated from a NOX4-like ancestor and is functional. Although no p22-phox was observed in arthropods, there was no evidence of neo-functionalization and this gene probably produces H2O2 as in other metazoan NOX4 genes. Although functional and present in the genomes of many species, NOX4-art was lost in a number of arthropod lineages.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-017-0940-0) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Evolutionary origin and function of NOX4-art, an arthropod specific NADPH oxidase

et al. 2017

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“…COS-7 and HEK-293 cells were grown in Dulbecco’s modified Eagle’s medium (DMEM) containing 100 U/ml penicillin, 100 mg/ ml streptomycin, and 10% FBS [28,29]. Human Lung Microvascular Endothelial Cells (HLMVECs) were isolated and grown in house as previously described [8,23] or purchased from Lonza and grown in Endothelial Growth Medium-2-Microvessel (EGM-2MV) containing the requisite growth factors and 5%FBS (Lonza, Allendale, NJ) and used below passage 8.…”

Section: Methodsmentioning

confidence: 99%

RhoA S-nitrosylation as a regulatory mechanism influencing endothelial barrier function in response to G + -bacterial toxins

Chen

Wang

Rafikov

et al. 2017

Biochemical Pharmacology

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Disruption of the endothelial barrier in response to Gram positive (G+) bacterial toxins is a major complication of acute lung injury (ALI) and can be further aggravated by antibiotics which stimulate toxin release. The integrity of the pulmonary endothelial barrier is mediated by the balance of disruptive forces such as the small GTPase RhoA, and protective forces including endothelium-derived nitric oxide (NO). How NO protects against the barrier dysfunction is incompletely understood and our goal was to determine whether NO and S-nitrosylation can modulate RhoA activity and whether this mechanism is important for G+ toxin-induced microvascular permeability. We found that the G+ toxin listeriolysin-O (LLO) increased RhoA activity and that NO and S-NO donors inhibit RhoA activity. RhoA was robustly S-nitrosylated as determined by biotin-switch and mercury column analysis. MS revealed that three primary cysteine residues are S-nitrosylated including cys16, cys20 and cys159. Mutation of these residues to serine diminished S-nitrosylation to endogenous NO and mutant RhoA was less sensitive to inhibition by S-NO. G+-toxins stimulated the denitrosylation of RhoA which was not mediated by S-nitrosoglutathione reductase (GSNOR), thioredoxin (TRX) or thiol-dependent enzyme activity but was instead stimulated directly by elevated calcium levels. Calcium-promoted the direct denitrosylation of WT but not mutant RhoA and mutant RhoA adenovirus was more effective than WT in disrupting the barrier integrity of human lung microvascular endothelial cells. In conclusion, we reveal a novel mechanism by which NO and S-nitrosylation reduces RhoA activity which may be of significance in the management of pulmonary endothelial permeability induced by G+-toxins.

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“…Diagram demonstrating structure of NOX5. NOX5 possesses six transmembrane domains with two haem‐binding sites, an N‐terminal domain with EF hands and a C‐terminal domain with phosphorylation sites (Bedard & Krause, ; Chen, Wang et al., ; Maghzal et al., ; Sedeek et al., )…”

Section: Introductionmentioning

confidence: 99%

NOX5: Molecular biology and pathophysiology

Touyz

Anagnostopoulou

Ríos

et al. 2019

Experimental Physiology

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New Findings What is the topic of this review? This review provides a comprehensive overview of Nox5 from basic biology to human disease and highlights unique features of this Nox isoform What advances does it highlight? Major advances in Nox5 biology relate to crystallization of the molecule and new insights into the pathophysiological role of Nox5. Recent discoveries have unravelled the crystal structure of Nox5, the first Nox isoform to be crystalized. This provides new opportunities to develop drugs or small molecules targeted to Nox5 in an isoform‐specific manner, possibly for therapeutic use. Moreover genome wide association studies (GWAS) identified Nox5 as a new blood pressure‐associated gene and studies in mice expressing human Nox5 in a cell‐specific manner have provided new information about the (patho) physiological role of Nox5 in the cardiovascular system and kidneys. Nox5 seems to be important in the regulation of vascular contraction and kidney function. In cardiovascular disease and diabetic nephropathy, Nox5 activity is increased and this is associated with increased production of reactive oxygen species and oxidative stress implicated in tissue damage. Abstract Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox), comprise seven family members (Nox1–Nox5 and dual oxidase 1 and 2) and are major producers of reactive oxygen species in mammalian cells. Reactive oxygen species are crucially involved in cell signalling and function. All Noxs share structural homology comprising six transmembrane domains with two haem‐binding regions and an NADPH‐binding region on the intracellular C‐terminus, whereas their regulatory systems, mechanisms of activation and tissue distribution differ. This explains the diverse function of Noxs. Of the Noxs, NOX5 is unique in that rodents lack the gene, it is regulated by Ca 2+ , it does not require NADPH oxidase subunits for its activation, and it is not glycosylated. NOX5 localizes in the perinuclear and endoplasmic reticulum regions of cells and traffics to the cell membrane upon activation. It is tightly regulated through numerous post‐translational modifications and is activated by vasoactive agents, growth factors and pro‐inflammatory cytokines. The exact pathophysiological significance of NOX5 remains unclear, but it seems to be important in the physiological regulation of sperm motility, vascular contraction and lymphocyte differentiation, and NOX5 hyperactivation has been implicated in cardiovascular disease, kidney injury and cancer. The field of NOX5 biology is still in its infancy, but with new insights into its biochemistry and cellular regulation, discovery of the NOX5 crystal structure and genome‐wide association studies implicating NOX5 in disease, the time is now ripe to advance NOX5 research. This review provides a comprehensive overview of our current understanding of NOX5, from basic ...

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Enzymatic regulation and functional relevance of NOX5

Cited by 29 publications

References 71 publications

Evolutionary origin and function of NOX4-art, an arthropod specific NADPH oxidase

Evolutionary origin and function of NOX4-art, an arthropod specific NADPH oxidase

RhoA S-nitrosylation as a regulatory mechanism influencing endothelial barrier function in response to G + -bacterial toxins

NOX5: Molecular biology and pathophysiology

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