Duox maturation factors form cell surface complexes with Duox affecting the specificity of reactive oxygen species generation

Morand, Stanislas; Ueyama, Takeshi; Tsujibe, Satoshi; Saito, Naoaki; Korzeniowska, Agnieszka; Leto, Thomas L.

doi:10.1096/fj.08-120006

Cited by 151 publications

(180 citation statements)

References 39 publications

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“…The DUOX1/ DUOXA1 genes are aligned head-to-head in a compressed genomic locus on chromosome 15, suggesting that expression of DUOX1 oxidase and its maturation factor are coordinated by a common bidirectional promoter (14). Several alternative splicing variants of DUOXA1 mRNA have been identified, and the lack of coding exon 6 has been shown to generate inactive forms of DUOXA1 (15).…”

Section: Resultsmentioning

confidence: 99%

NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation

Ameziane-El-Hassani

Talbot

Santos

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

109

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Ionizing radiation (IR) causes not only acute tissue damage, but also late effects in several cell generations after the initial exposure. The thyroid gland is one of the most sensitive organs to the carcinogenic effects of IR, and we have recently highlighted that an oxidative stress is responsible for the chromosomal rearrangements found in radio-induced papillary thyroid carcinoma. Using both a human thyroid cell line and primary thyrocytes, we investigated the mechanism by which IR induces the generation of reactive oxygen species (ROS) several days after irradiation. We focused on NADPH oxidases, which are specialized ROS-generating enzymes known as NOX/DUOX. Our results show that IR induces delayed NADPH oxidase DUOX1-dependent H 2 O 2 production in a dose-dependent manner, which is sustained for several days. We report that p38 MAPK, activated after IR, increased DUOX1 via IL-13 expression, leading to persistent DNA damage and growth arrest. Pretreatment of cells with catalase, a scavenger of H 2 O 2 , or DUOX1 down-regulation by siRNA abrogated IR-induced DNA damage. Analysis of human thyroid tissues showed that DUOX1 is elevated not only in human radio-induced thyroid tumors, but also in sporadic thyroid tumors. Taken together, our data reveal a key role of DUOX1-dependent H 2 O 2 production in long-term persistent radio-induced DNA damage. Our data also show that DUOX1-dependent H 2 O 2 production, which induces DNA double-strand breaks, can cause genomic instability and promote the generation of neoplastic cells through its mutagenic effect.ionizing radiation | oxidative stress | NADPH oxidase | thyroid |

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Section: Resultsmentioning

confidence: 99%

NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation

Ameziane-El-Hassani

Talbot

Santos

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

109

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“…The H 2 O 2 production by DUOX2 requires a maturation factor (DUOXA2) that is co-expressed with DUOX2 and permits the translocation of DUOX2 from the endoplasmic reticulum to the Golgi apparatus, and its subsequent maturation and translocation to the apical membrane. Recent studies revealed that the expression of Duox2 mRNA is rapidly stimulated by TSH through the cAMP pathway in human, porcine, canine, and FRTL-5 cells (1,4,23,50).…”

Section: Discussionmentioning

confidence: 99%

“…H 2 O 2 is produced by two isoform enzymes, DUOX1 and DUOX2, which were initially identified in the thyroid as nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) that produce H 2 O 2 , either by direct generation or through the production of O 2 -as a precursor (1)(2)(3)(4). The activities of NOX/DUOX are regulated at the level of enzyme assembly.…”

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confidence: 99%

Regulation of Dual Oxidase Expression and H₂O₂Production by Thyroglobulin

Yoshihara

Hara

Kawashima

et al. 2012

Thyroid

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Background: Thyroglobulin (Tg) is a macromolecular precursor in thyroid hormone synthesis to which iodine is stably bound. Tg, which is stored in the follicular space, is also a potent negative feedback regulator of follicular function, and this is achieved by suppressing mRNA levels of thyroid-specific genes such as the sodium/iodide symporter (Slc5a5), Tg, and thyroid peroxidase. Dual oxidase 1 (DUOX1) and DUOX2, originally identified in the thyroid, are nicotinamide adenine dinucleotide phosphate (NADPH) oxidases that are necessary to produce the H 2 O 2 required for thyroid hormone biosynthesis. Since follicular Tg regulates the expression of genes that are essential for thyroid hormone synthesis, we hypothesized that Tg might also regulate DUOX expression and H 2 O 2 production. Methods: Rat thyroid FRTL-5 cells were treated with Tg, and the mRNA expression of Duox1 and Duox2 and their corresponding maturation factors Duoxa1 and Duoxa2 were evaluated by DNA microarray and real-time PCR. Duox2 promoter activity was examined by luciferase reporter gene assay. Protein levels of DUOX2 were also examined by Western blot analysis. Intracellular H 2 O 2 generation was quantified by a fluorescent dye, 5-(and-6)-chloromethyl-2¢,7¢-dichlorodihydrofluorescein diacetate, and acetyl ester (CM-H 2 DCFDA). Results: mRNA levels of Duox2 and its activation factor Duoxa2 (but not Duox1 or Duoxa1) were significantly suppressed by Tg in a dose-dependent manner and a time-dependent fashion in rat thyroid FRTL-5 cells. DUOX2 promoter activity was significantly suppressed by Tg in a dose-dependent manner. Protein levels of DUOX2 and H 2 O 2 generation in cells were also reduced by Tg treatment. Conclusions: We show that physiological concentrations of Tg suppressed the expression and function of DUOX2 in thyroid cells. These results suggest that Tg is a strong suppressor of the expression and the activity of DUOX2/DUOXA2, thereby regulating iodide organification and hormone synthesis in the thyroid. The evidence supports a reported model in which accumulated Tg in thyroid follicles plays important roles in autoregulating the function of individual follicles, which produces the basis of follicular heterogeneity.

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“…This suggests that DUOX1 may be active in lung tissue but requires other protein interactions for maturation (DUOXA1), transport, or activity (59,60). Recently, the DUOX maturation factors (DUOXA1 and DUOXA2) were shown to form stable cell surface complexes with the DUOX proteins and may function as part of a H 2 O 2 -generating enzyme complex (61). Co-expression of hDUOX1 in the presence of DUOXA1 or pull-down assays of the peroxidase domain with mammalian cell lysates may provide a better understanding of any specific protein interactions that modulate DUOX1 activity.…”

Section: Discussionmentioning

confidence: 99%

Caenorhabditis elegans and Human Dual Oxidase 1 (DUOX1) “Peroxidase” Domains

Meitzler

Montellano

2009

Journal of Biological Chemistry

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The seven members of the NOX/DUOX family are responsible for generation of the superoxide and H 2 O 2 required for a variety of host defense and cell signaling functions in nonphagocytic cells. Two members, the dual oxidase isozymes DUOX1 and DUOX2, share a structurally unique feature: an N-terminal peroxidase-like domain. Despite sequence similarity to the mammalian peroxidases, the absence of key active site residues makes their binding of heme and their catalytic function uncertain. To explore this domain we have expressed in a baculovirus system and purified the Caenorhabditis elegans (CeDUOX1 1-589 ) and human (hDUOX1 1-593 ) DUOX1 "peroxidase" domains. Evaluation of these proteins demonstrated that the isolated hDUOX1 1-593 does not bind heme and has no intrinsic peroxidase activity. In contrast, CeDUOX1 1-589 binds heme covalently, exhibits a modest peroxidase activity, but does not oxidize bromide ion. Surprisingly, the heme appears to have two covalent links to the protein despite the absence of a second conserved carboxyl group in the active site. Although the N-terminal dual oxidase motif has been proposed to directly convert superoxide to H 2 O 2 , neither DUOX1 domain demonstrated significant superoxide dismutase activity. These results strengthen the in vivo conclusion that the CeDUOX1 protein supports controlled peroxidative polymerization of tyrosine residues and indicate that the hDUOX1 protein either has a unique function or must interact with other protein factors to express its catalytic activity.

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Duox maturation factors form cell surface complexes with Duox affecting the specificity of reactive oxygen species generation

Cited by 151 publications

References 39 publications

NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation

NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation

Regulation of Dual Oxidase Expression and H₂O₂Production by Thyroglobulin

Caenorhabditis elegans and Human Dual Oxidase 1 (DUOX1) “Peroxidase” Domains

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Duox maturation factors form cell surface complexes with Duox affecting the specificity of reactive oxygen species generation

Cited by 151 publications

References 39 publications

NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation

NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation

Regulation of Dual Oxidase Expression and H2O2Production by Thyroglobulin

Caenorhabditis elegans and Human Dual Oxidase 1 (DUOX1) “Peroxidase” Domains

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Regulation of Dual Oxidase Expression and H₂O₂Production by Thyroglobulin