Interaction between p22phox and Nox4 in the endoplasmic reticulum suggests a unique mechanism of NADPH oxidase complex formation

Zana, Melinda; Péterfi, Zalán; Kovács, Hajnal A.; Tóth, Zsuzsanna; Enyedi, Balázs; Morel, Françoise; Paclet, Marie-Hélène; Donkó, Ágnes; Morand, Stanislas; Leto, Thomas L.; Geiszt, Miklós

doi:10.1016/j.freeradbiomed.2017.12.031

Cited by 32 publications

(22 citation statements)

References 41 publications

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“…An important shared feature of NOX1, NOX2, NOX3, and NOX4 is that their activity is dependent on the co-expression of the p22 phox protein [1] , [21] . The nmf333 mouse strain carries a mutation in the p22 phox gene, which leads to the destabilization of the protein with a consequent loss of Nox2 and Nox4 activity [23] , [40] . Testing collagen IV crosslinking in this strain offered us the possibility to study the possible involvement of four different NOX isoforms simultaneously, although the uniquely limited expression pattern of NOX3 made unlikely that this particular isoform contributes to the formation of sulfilimine linkages.…”

Section: Resultsmentioning

confidence: 99%

Peroxidasin-mediated crosslinking of collagen IV is independent of NADPH oxidases

et al. 2018

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Collagen IV is a major component of the basement membrane in epithelial tissues. The NC1 domains of collagen IV protomers are covalently linked together through sulfilimine bonds, the formation of which is catalyzed by peroxidasin. Although hydrogen peroxide is essential for this reaction, the exact source of the oxidant remains elusive. Members of the NOX/DUOX NADPH oxidase family are specifically devoted to the production of superoxide and hydrogen peroxide. Our aim in this study was to find out if NADPH oxidases contribute in vivo to the formation of collagen IV sulfilimine crosslinks. We used multiple genetically modified in vivo model systems to provide a detailed assessment of this question. Our data indicate that in various peroxidasin-expressing tissues sulfilimine crosslinks between the NC1 domains of collagen IV can be readily detected in the absence of functioning NADPH oxidases. We also analyzed how subatmospheric oxygen levels influence the collagen IV network in collagen-producing cultured cells with rapid matrix turnover. We showed that collagen IV crosslinks remain intact even under strongly hypoxic conditions. Our hypothesis is that during collagen IV network formation PXDN cooperates with a NOX/DUOX-independent H2O2 source that is functional also at very low ambient oxygen levels.

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Section: Resultsmentioning

confidence: 99%

Peroxidasin-mediated crosslinking of collagen IV is independent of NADPH oxidases

et al. 2018

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“…p47phox and p67phox) [20,23]. Translocation of p47phox and p67phox from the cytoplasm to the membrane is essential for the activation of NADPH [23]. Western blotting showed that p47phox and p67phox were indeed mainly distributed in the cytoplasm of HT22 cells.…”

Section: Trpc1 Preventes Ogd/r-induced P47phox and P67phox Translocationmentioning

confidence: 99%

“…Nox2-containing NADPH oxidase is a classic multisubunit complex that contains two plasma membrane subunits-Nox2 and p22phox-and three cytosolic subunits-p47phox, p67phox, and Rac1 [21]. In addition to the interaction between Nox2 and p22phox, a recent study showed that Nox4 also interacts with p22phox [23]. On the basis of this finding, we investigated whether TRPC1 affects NADPH complex assembly.…”

Section: Cellular Physiology and Biochemistry Cellular Physiology Andmentioning

confidence: 99%

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TRPC1 Deficiency Exacerbates Cerebral Ischemia/Reperfusion-Induced Neurological Injury by Potentiating Nox4-Derived Reactive Oxygen Species Generation

Meng

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Transient receptor potential cation channel 1 (TRPC1)-mediated the calcium (Ca²⁺) influx plays an important role in several brain disorders. However, the function of TRPC1 in ischemia/reperfusion (I/R)-induced neurological injury is unclear. Methods: Wild-type or TRPC1 knockout mice underwent middle cerebral artery occlusion for 90 min followed by 24 h of reperfusion. In an in vitro study, neuronal cells were treated with oxygen–glucose deprivation and reoxygenation (OGD/R) to mimic I/R. The intracellular Ca²⁺ concentration [Ca²⁺]_i was measured by Fura 2-AM under a microscope. Cerebral infarct volume was measured by triphenyltetrazolium chloride staining. Neurological function was examined by neurological severity score, Morris water maze test, rotarod test and string test. Oxidative parameters were detected by malondialdehyde, glutathione peroxidase, and superoxide dismutase commercially available kits. The protein expression levels of TRPC1, Nox4, p22phox, p47phox, and p67phox were analyzed by western blotting. Results: Brain tissues from cerebral I/R mice showed decreased TRPC1 expression. Similarly, TRPC1 expression was reduced in HT22 cells upon exposure to OGD/R treatment, followed by decreased Ca²⁺ influx. However, TRPC1 overexpression reversed the OGD/R-induced decrease in [Ca²⁺]_i. TRPC1 knockout significantly exacerbated I/R-induced brain infarction, edema, neurological severity score, memory impairment, neurological deficits, and oxidative stress. In contrast, TRPC1 upregulation inhibited the increase in reactive oxygen species (ROS) generation induced by OGD/R. Analysis of key subunits of the Nox family and mitochondrial ROS revealed that the effects of TRPC1 downregulation on oxidative stress were associated with activation of Nox4-containing NADPH oxidase. TRPC1 interacted with Nox4 and facilitated Nox4 protein degradation under OGD/R conditions. In addition, TRPC1 inhibition potentiated the OGD/R-induced translocation of p47phox and p67phox as well as the interaction between Nox4 and p47phox or p67phox, whereas TRPC1 overexpression had the opposite effects. Conclusion: TRPC1 deficiency potentiates ROS generation via Nox4-containing NADPH oxidase, which exacerbates cerebral I/R injury. TRPC1 may be a promising molecular target for the treatment of stroke.

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“…PDI is also involved in H 2 O 2 generation through interconnections with NOX1 and NOX4, which belong to the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase protein family [81, 82]. In addition, NOX4 occurs in the NOX4-p22 phox complex in the ER membrane and is involved in releasing H 2 O 2 in the ER lumen [83]. One more site of ROS generation in the ER is the microsomal monooxygenase (MMO) system.…”

Section: Sources Of Ros Generation and Antioxidant Defense Systemsmentioning

confidence: 99%

ROS Generation and Antioxidant Defense Systems in Normal and Malignant Cells

Snezhkina

Kudryavtseva

Kardymon

et al. 2019

Oxidative Medicine and Cellular Longevity

658

424

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Reactive oxygen species (ROS) are by-products of normal cell activity. They are produced in many cellular compartments and play a major role in signaling pathways. Overproduction of ROS is associated with the development of various human diseases (including cancer, cardiovascular, neurodegenerative, and metabolic disorders), inflammation, and aging. Tumors continuously generate ROS at increased levels that have a dual role in their development. Oxidative stress can promote tumor initiation, progression, and resistance to therapy through DNA damage, leading to the accumulation of mutations and genome instability, as well as reprogramming cell metabolism and signaling. On the contrary, elevated ROS levels can induce tumor cell death. This review covers the current data on the mechanisms of ROS generation and existing antioxidant systems balancing the redox state in mammalian cells that can also be related to tumors.

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Interaction between p22phox and Nox4 in the endoplasmic reticulum suggests a unique mechanism of NADPH oxidase complex formation

Abstract: ABSTRACT

Cited by 32 publications

References 41 publications

Peroxidasin-mediated crosslinking of collagen IV is independent of NADPH oxidases

Peroxidasin-mediated crosslinking of collagen IV is independent of NADPH oxidases

TRPC1 Deficiency Exacerbates Cerebral Ischemia/Reperfusion-Induced Neurological Injury by Potentiating Nox4-Derived Reactive Oxygen Species Generation

ROS Generation and Antioxidant Defense Systems in Normal and Malignant Cells

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