Article

Downstream Targets and Intracellular Compartmentalization in Nox Signaling

Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School Worcester, Massachusetts 01605, USA.
Antioxidants & Redox Signaling (Impact Factor: 7.67). 04/2009; 11(10):2467-80. DOI: 10.1089/ARS.2009.2594
Source: PubMed

ABSTRACT Reactive oxygen species (ROS) have become recognized for their role as second messengers in a multitude of physiologic responses. Emerging evidence points to the importance of the NADPH oxidase family of ROS-producing enzymes in mediating redox-sensitive signal transduction. However, a clear paradox exists between the specificity required for signaling and the nature of ROS as both diffusible and highly reactive molecules. We seek to understand the targets and compartmentalization of the NADPH oxidase signaling to determine how NADPH oxidase-derived ROS fit into established signaling paradigms. Herein we review recent data that link cellular NADPH oxidase enzymes to ROS signaling, with a particular focus on the mechanism(s) involved in achieving signaling specificity.

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Available from: Siobhan M Craige, Aug 11, 2015
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    • "The NOX family of NADPH oxidase enzymes are membrane-bound electron carriers, which use NADPH as electron donor and oxygen as acceptor. NADPH oxidases localize to cellular membrane compartments via targeting proteins, facilitating hydrogen peroxide (H 2 O 2 ) production within spatially confined areas [31] [35]. There are various molecular mechanisms within a cell designed to counteract overproduction of ROS. "
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    ABSTRACT: Oxidative stress damages multiple cellular components including DNA, lipids, and proteins and has been linked to pathological alterations in nonalcoholic fatty liver disease (NAFLD). Reactive oxygen species (ROS) emission, resulting from nutrient overload and mitochondrial dysfunction, is thought to be a principal mediator in NAFLD progression, particularly toward the development of hepatic insulin resistance. In the context of insulin signalling, ROS has a dual role, as both a facilitator and inhibitor of the insulin signalling cascade. ROS mediate these effects through redox modifications of cysteine residues affecting phosphatase enzyme activity, stress-sensitive kinases, and metabolic sensors. This review highlights the intricate relationship between redox-sensitive proteins and insulin signalling in the context of fatty liver disease, and to a larger extent, the importance of reactive oxygen species as primary signalling molecules in metabolically active cells.
    International Journal of Cell Biology 02/2014; 2014(1):519153. DOI:10.1155/2014/519153
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    • "However , in non-innate immune cells, ROS are more often associated with oxidative stress, as chronic imbalance in the cellular reduction–oxidation (redox) state is implicated in various diseases, including vascular thrombosis [1] [2]. ROS also represent important secondary messengers in signal transduction cascades through their ability to oxidatively modify protein thiols, such as catalytic cysteinyl residues in protein tyrosine phosphatases, or interact with other reactive compounds [3] [4]. As activated platelets produce predominantly intracellular ROS; platelet-derived ROS are believed to have a role in regulating cellular function rather than providing a physiological response to pathogen invasion [5] [6]. "
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    ABSTRACT: Activation of the platelet-specific collagen receptor, glycoprotein (GP) VI, induces intracellular reactive oxygen species (ROS) production; however the relevance of ROS to GPVI-mediated platelet responses remains unclear. The objective of this study was to explore the role of the ROS-producing NADPH oxidase (Nox)1 and 2 complexes in GPVI-dependent platelet activation and collagen-induced thrombus formation. ROS production was measured by quantitating changes in the oxidation-sensitive dye, H2DCF-DA, following platelet activation with the GPVI-specific agonist, collagen related peptide (CRP). Using a pharmacological inhibitor specific for Nox1, 2-acetylphenothiazine (ML171), and Nox2 deficient mice, we show that Nox1 is the key Nox homolog regulating GPVI-dependent ROS production. Nox1, but not Nox2, was essential for CRP-dependent thromboxane (Tx)A2 production, which was mediated in part through p38 MAPK signaling; while neither Nox1 nor Nox2 was significantly involved in regulating CRP-induced platelet aggregation/integrin αIIbβ3 activation, platelet spreading, or dense granule and α-granule release (ATP release and P-selectin surface expression, respectively). Ex-vivo perfusion analysis of mouse whole blood revealed that both Nox1 and Nox2 were involved in collagen-mediated thrombus formation at arterial shear. Together these results demonstrate a novel role for Nox1 in regulating GPVI-induced ROS production, which is essential for optimal p38 activation and subsequent TxA2 production, providing an explanation for reduced thrombus formation following Nox1 inhibition.
    01/2014; 2(1):178-86. DOI:10.1016/j.redox.2013.12.023
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    • "In mammalian cells, membrane-bound nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) transfer electrons from NADPH to oxygen molecules via flavin adenine dinucleotides (FAD) and iron, leading to the production of superoxide, which is rapidly converted to H 2O2 by SOD (Chen et al., 2009; Cheng et al., 2006; Vignais, 2002). Nox homologues, which are widely found in animals, plants and many multicellular microorganisms, yet completely absent in prokaryotes, have a vital role in both cellular differentiation and the defence response. "
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    ABSTRACT: The fungal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) complex, which has been implicated in the production of low-level reactive oxygen species (ROS), contains mainly NoxA, NoxB (gp91(phox) homologues) and NoxR (p67(phox) homologue). Here, we report the developmental and pathological functions of NoxB and NoxR in the tangerine pathotype of Alternaria alternata. Loss-of-function genetics revealed that all three Nox components are required for the accumulation of cellular hydrogen peroxide (H2 O2 ). Alternaria alternata strains lacking NoxA, NoxB or NoxR also displayed an increased sensitivity to H2 O2 and many ROS-generating oxidants. These phenotypes are highly similar to those previously seen for the Δyap1 mutant lacking a YAP1 transcriptional regulator and for the Δhog1 mutant lacking a HOG1 mitogen-activated protein (MAP) kinase, implicating a possible link among them. A fungal strain carrying a NoxA NoxB or NoxA NoxR double mutation was more sensitive to the test compounds than the strain mutated at a single gene, implicating a synergistic function among Nox components. The ΔnoxB mutant strain failed to produce any conidia; both ΔnoxA and ΔnoxR mutant strains showed a severe reduction in sporulation. Mutant strains carrying defective NoxB had higher chitin content than the wild-type and were insensitive to calcofluor white, Congo red and the fungicides vinclozolin and fludioxonil. Virulence assays revealed that all three Nox components are required for the elaboration of the penetration process. The inability to penetrate the citrus host, observed for Δnox mutants, could be overcome by wounding and by reacquiring a dominant Nox gene. The A. alternata NoxR did not influence the expression of NoxB, but negatively regulated NoxA. Importantly, the expression of both YAP1 and HOG1 genes, whose products are involved in resistance to ROS, was down-regulated in fungi carrying defective NoxA, NoxB or NoxR. Our results highlight the requirement of Nox in ROS resistance and provide insights into its critical role in regulating both YAP1 and HOG1 in A. alternata.
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