Nrf2 and selenoproteins are essential for maintaining oxidative homeostasis in erythrocytes and protecting against hemolytic anemia

Kawatani, Yukie; Suzuki, Takafumi; Shimizu, Ritsuko; Kelly, Vincent P.; Yamamoto, Masayuki

doi:10.1182/blood-2010-05-285817

Cited by 60 publications

(50 citation statements)

References 41 publications

(48 reference statements)

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“…30 To date, 2 nonredundant Foxo3 and Nrf2-mediated pathways to combat oxidative stress have been identified in erythroid cells. [31][32][33] We show here for the first time that the Hri-eIF2␣P-Atf4 pathway is also required in the erythroid lineage for the adaptation to oxidative stress.…”

Section: Discussionmentioning

confidence: 93%

Heme-regulated eIF2α kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis

Suragani

Zachariah

Velazquez

et al. 2012

Blood

153

162

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Heme-regulated eIF2␣ kinase (Hri) is necessary for balanced synthesis of heme and globin. In addition, Hri deficiency exacerbates the phenotypic severity of ␤-thalassemia intermedia in mice. Activation of Hri during heme deficiency and in ␤-thalassemia increases eIF2␣ phosphorylation and inhibits globin translation. Under endoplasmic reticulum stress and nutrient starvation, eIF2␣ phosphorylation also induces the Atf4 signaling pathway to mitigate stress. Although the function of Hri in regulating globin translation is well established, its role in Atf4 signaling in erythroid precursors is not known. Here, we report the role of the Hriactivated Atf4 signaling pathway in reducing oxidative stress and in promoting erythroid differentiation during erythropoiesis. On acute oxidative stress, Hri Ϫ/Ϫ erythroblasts suffered from increased levels of reactive oxygen species (ROS) and apoptosis. During chronic iron deficiency in vivo, Hri is necessary both to reduce oxidative stress and to promote erythroid differentiation. Hri Ϫ/Ϫ mice developed ineffective erythropoiesis during iron deficiency with inhibition of differentiation at the basophilic erythroblast stage. This inhibition is recapitulated during ex vivo differentiation of Hri Ϫ/Ϫ fetal liver erythroid progenitors. Importantly, the HrieIF2␣P-Atf4 pathway was activated and required for erythroid differentiation. We further demonstrate the potential of modulating Hri-eIF2␣P-Atf4 signaling with chemical compounds as pharmaceutical therapies for ␤-thalassemia. IntroductionHeme-regulated eIF2␣ kinase (Hri) was the first discovered member of the family of eIF2␣ kinases, which control translational initiation under diverse stress conditions by phosphorylation of the ␣-subunit of eIF2 (eIF2␣P). 1,2 Hri is necessary to coordinate translation of globin mRNAs with the availability of heme for the production of large amounts of hemoglobin during erythroid maturation. 3 In Hri deficiency, excessive globins synthesized during heme deficiency precipitate and form inclusions causing proteotoxicity. 3,4 Beyond heme deficiency, Hri is also activated by oxidative stress and denatured proteins, 5 both of which occur in thalassemia. 6 Indeed, Hri is required to reduce the phenotypic severity of the Hbb Ϫ/Ϫ mouse model of ␤-thalassemia intermedia lacking both copies of ␤-globin major. 4 Besides Hri, there are 3 additional mammalian eIF2␣ kinases: the double-stranded RNA-dependent eIF2␣ kinase (Pkr), the Gcn2 protein kinase, and the Pkr-like ER resident kinase (Perk). 1 Each kinase elicits a major physiologic response in vivo: Pkr responds to viral infection; Gcn2 senses nutrient starvations; Perk is activated by endoplasmic reticulum (ER) stress; and Hri is regulated by heme. In addition to inhibition of global protein synthesis, the second function of eIF2␣ phosphorylation is to reprogram translation and transcription necessary for adaptation to stress 7 as illustrated in Figure 7A. In mammalian cells, translation of activating transcriptional factor 4 (Atf4) is selectively increas...

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Section: Discussionmentioning

confidence: 93%

Heme-regulated eIF2α kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis

Suragani

Zachariah

Velazquez

et al. 2012

Blood

153

162

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“…Selenoprotein deficiency in the liver activates the hepatoprotective Nrf2 response and increases susceptibility to diethylnitrosamine (DEN)-induced tumorigenesis (101,105,106). Similarly, hematopoietic-specific loss of selenoproteins leads to oxidative stress, hemolytic anemia, and sustained activation of Nrf2 (107,108). Prostate-specific trsp KO mice exhibit prostate neoplasia, demonstrating that selenoproteins function as tumor suppressors in the murine prostate (109,110).…”

Section: Discussionmentioning

confidence: 99%

Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis

Cox

Tsomides

Kim

et al. 2016

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

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Selenium, an essential micronutrient known for its cancer prevention properties, is incorporated into a class of selenocysteine-containing proteins (selenoproteins). Selenoprotein H (SepH) is a recently identified nucleolar oxidoreductase whose function is not well understood. Here we report that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling by targeted LC-MS/MS demonstrated that SepH deficiency impairs redox balance by reducing the levels of ascorbate and methionine, while increasing methionine sulfoxide. Transcriptome analysis revealed that SepH deficiency induces an inflammatory response and activates the p53 pathway. Consequently, loss of seph renders larvae susceptible to oxidative stress and DNA damage. Finally, we demonstrate that seph interacts with p53 deficiency in adulthood to accelerate gastrointestinal tumor development. Overall, our findings establish that seph regulates redox homeostasis and suppresses DNA damage. We hypothesize that SepH deficiency may contribute to the increased cancer risk observed in cohorts with low selenium levels.

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“…In addition, erythroid precursors may be also subjected to diverse stresses in bone marrow, such as hypoxia, mechanical stress, radiation, foreign chemicals and environmental toxicants [23][24][25][26]. Thus, an elegant network has evolved to protect erythroid cells during differentiation, including translation control to prevent hemoglobin aggregating by heme-regulated eIF2α kinase (HRI), ATF4 signaling against oxidative stress and Nrf2 signaling-mediated protection, etc [22,27]. ATF4 is a key transcriptional factor involved in cytoprotection upon stresses, such as unfolded protein response, amino acids and oxidative stress, and ATF4 activation is a part of integrated stress response network [28,29].…”

Section: Introductionmentioning

confidence: 99%

miR-214 protects erythroid cells against oxidative stress by targeting ATF4 and EZH2

Gao

Liu

Chen

et al. 2016

Free Radical Biology and Medicine

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Nrf2 and selenoproteins are essential for maintaining oxidative homeostasis in erythrocytes and protecting against hemolytic anemia

Cited by 60 publications

References 41 publications

Heme-regulated eIF2α kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis

Heme-regulated eIF2α kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis

Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis

miR-214 protects erythroid cells against oxidative stress by targeting ATF4 and EZH2

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