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Selenoprotein H Is an Essential Regulator of Redox Homeostasis That

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Selenoprotein H Is an Essential Regulator of Redox Homeostasis That Selenoprotein H is an essential regulator of redox PNAS PLUS homeostasis that cooperates with p53 in development and tumorigenesis Andrew G. Coxa, Allison Tsomidesa, Andrew J. Kima, Diane Saundersa, Katie L. Hwanga, Kimberley J. Evasonb, Jerry Heidelc, Kristin K. Brownd, Min Yuand, Evan C. Liend, Byung Cheon Leea,e, Sahar Nissima, Bryan Dickinsonf, Sagar Chhangawalag, Christopher J. Changh,i, John M. Asarad, Yariv Houvrasg, Vadim N. Gladysheva,j, and Wolfram Goesslinga,j,k,l,1 aBrigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; bUniversity of Utah, Salt Lake City, UT 84112; cOregon State University, Corvallis, OR 97331; dBeth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115; eKorea University, 02841 Seoul, Republic of Korea; fUniversity of Chicago, Chicago, IL 60637; gWeill Cornell Medical College and New York Presbyterian Hospital, New York, NY 10065; hHoward Hughes Medical Institute, Bethesda, MD 20815; iUniversity of California, Berkeley, CA 20815; jBroad Institute of MIT and Harvard, Cambridge, MA 02142; kHarvard Stem Cell Institute, Cambridge, MA 02138; and lDana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 Edited by Leonard I. Zon, Howard Hughes Medical Institute, Boston Children’s Hospital, Harvard Medical School, Boston, MA, and accepted by Editorial Board Member Carol Prives July 18, 2016 (received for review January 7, 2016) Selenium, an essential micronutrient known for its cancer preven- mice exhibit impaired selenium transport from the liver to pe- tion properties, is incorporated into a class of selenocysteine- ripheral tissues and show growth retardation and impaired motor containing proteins (selenoproteins). Selenoprotein H (SepH) is a coordination (13, 14). In contrast, mice deficient in Gpx1 (15), recently identified nucleolar oxidoreductase whose function is not Gpx2 (16), Gpx3 (17), MsrB1 (18), Sep15 (19), or SelM (20) are well understood. Here we report that seph is an essential gene viable, with more subtle defects, some of which only manifest in regulating organ development in zebrafish. Metabolite profiling the context of stress. by targeted LC-MS/MS demonstrated that SepH deficiency impairs Epidemiologic surveys have shown that selenium deficiency BIOLOGY redox balance by reducing the levels of ascorbate and methionine, may be associated with an increased risk of certain types of cancer DEVELOPMENTAL while increasing methionine sulfoxide. Transcriptome analysis (21, 22). For example, patients with cirrhosis (scarring) of the liver revealed that SepH deficiency induces an inflammatory response have a high risk of developing liver cancer, and are typically de- seph and activates the p53 pathway. Consequently, loss of renders ficient in selenium (23–26). However, selenium supplementation larvae susceptible to oxidative stress and DNA damage. Finally, we chemoprevention trials have provided mixed results, possibly re- demonstrate that seph interacts with p53 deficiency in adulthood lated to a combination of unknown baseline selenium status and to accelerate gastrointestinal tumor development. Overall, our genetic factors that modulate selenoprotein function (22). In vivo findings establish that seph regulates redox homeostasis and sup- presses DNA damage. We hypothesize that SepH deficiency may cancer studies using transgenic mice have revealed that the role contribute to the increased cancer risk observed in cohorts with of selenoproteins in tumorigenesis is context-dependent, both low selenium levels. preventing and promoting cancer (27, 28). The importance of selenium | selenoproteins | p53 | liver cancer | endoderm development Significance elenium is an essential micronutrient that has been impli- Dietary selenium and selenoproteins play important roles in Scated in cancer chemoprevention and is thought to delay the regulating redox processes that impact human health. The hu- severity of cardiovascular and neurologic disorders (1). The bi- man genome includes 25 genes for selenoproteins, which have ological properties of selenium are mediated by a diverse group diverse roles in redox homeostasis, thyroid hormone metabo- of selenocysteine (Sec)-containing selenoproteins (2). Sec is in- lism, endoplasmic reticulum quality control, selenium transport, corporated into protein in response to the UGA opal codon in a and other functions. Selenoprotein H (seph) is a recently iden- unique context in which the 3′ UTR of the gene contains a Sec tified nucleolar oxidoreductase with DNA-binding properties insertion sequence (SECIS) element (3, 4). The human seleno- whose function is not well understood. In this work, we used proteome includes five glutathione peroxidases (GPX1-4, 6), a unique combination of unbiased metabolomic and tran- three thioredoxin reductases (TXNRD1-3), and one methionine scriptomic approaches in zebrafish to discover that seph is an sulfoxide reductase (MSRB1) that act in concert to provide an- essential regulator of redox homeostasis that regulates p53. In tioxidant defense (2). The selenoproteome also includes three addition, we demonstrate the seph-deficient adults are prone to iodothyronine deiodinases (DIO1-3) that control thyroid hor- chemically induced carcinogenesis. Our results suggest that seph mone metabolism and two selenoproteins that are involved in suppresses oxidative stress and DNA damage in the nucleolus. selenoprotein synthesis (SPS2) and transport (SELP). In con- trast, little is known regarding the function of the other 11 human Author contributions: A.G.C. and W.G. designed research; A.G.C., A.T., A.J.K., D.S., K.L.H., K.J.E., J.H., K.K.B., M.Y., E.C.L., B.C.L., and S.N. performed research; B.D. and C.J.C. con- selenoproteins (SELW, SELT, SELH, SELV, SELI, SEP15, tributed new reagents/analytic tools; A.G.C., A.T., K.J.E., J.H., K.K.B., M.Y., E.C.L., S.C., J.M.A., SELM, SELK, SELS, SELO, and SELN) (5). Y.H., V.N.G., and W.G. analyzed data; C.J.C., J.M.A., Y.H., and V.N.G. provided general input Although selenium was originally considered a toxin, classic on study design and analysis; and A.G.C. and W.G. wrote the paper. work by Schwartz and Foltz showed that selenium prevents liver The authors declare no conflict of interest. necrosis in rats, suggesting that it is an essential micronutrient This article is a PNAS Direct Submission. L.I.Z. is a Guest Editor invited by the (6). This essential role as a micronutrient during development Editorial Board. Data deposition: The data reported in this paper have been deposited in the Gene Ex- was subsequently recognized by the livestock industry and is now pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE85943). widely known for human health (7). Genetic disruption of three 1To whom correspondence should be addressed. Email: [email protected]. ― ― mammalian selenoproteins GPX4, TXNRD1, and TXNRD2 This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. causes embryonic lethality (8–12) in murine models. SelP-deficient 1073/pnas.1600204113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1600204113 PNAS Early Edition | 1of10 Downloaded by guest on September 30, 2021 selenium and selenoproteins in embryonic development and tu- the differences in Sec incorporation efficiency and nonsense-medi- morigenesis underscores the need for a better understanding of ated decay (30, 31). the biological function of the recently identified selenoproteins. Developmental defects in homozygous seph mutants begin to Here we show that seph (ortholog of human SELH) plays an manifest morphologically by 3 d postfertilization (dpf), and the essential role in vertebrate organ development. Using unbiased mutants lose viability by 12–14 dpf (Fig. 1B). At 5 dpf, seph metabolomic and transcriptomic approaches, we found that SepH mutants exhibit craniofacial defects with smaller eyes (micro- deficiency alters redox homeostasis, provokes an inflammatory phthalmia), impaired yolk absorption, and an uninflated swim response, and activates p53. SepH-deficient zebrafish larvae ex- bladder (Fig. 1C). To examine the effect of SepH deficiency on hibit an increased susceptibility to oxidative stress and DNA endodermal organ development, we imaged seph mutants on damage. Loss of p53 partially mitigates the developmental defects transgenic reporter fish, highlighting the liver and exocrine observed in seph mutants; however, loss of p53 function combines pancreas [Tg(ela3l:GFP;fabp10a:dsRed)] at 5 dpf, which revealed with SepH haploinsufficiency in adulthood to accelerate gas- dramatically impaired liver and pancreas development (Fig. 1C). trointestinal (GI) tumor development. Collectively, our results Quantification of liver and pancreas fluorescence revealed that the seph mutant liver was ∼40% smaller than WT liver, whereas establish that SepH regulates redox homeostasis and suppresses the pancreas was almost absent (Fig. 1 D and E). Similarly, we DNA damage during development and tumorigenesis. assessed organ development in Tg(gata6:GFP), which highlights Results endodermal organs, and Tg(fabp2:dsRed), which illuminates the intestinal epithelium of larvae, and this confirmed that seph mu- seph Mutant Zebrafish Exhibit Defects in Organ Development. This tants exhibit defects in intestinal development (Fig. S1 C and D). investigation was spurred by the isolation of a seph mutant from To confirm that the loss of seph gene function induced by a large-scale insertional mutagenesis screen (29). This seph disruption of the SECIS element
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