Secisbp2 is essential for embryonic development and enhances selenoprotein expression

Abstract

Aims: The selenocysteine insertion sequence (SECIS)-binding protein 2 (Secisbp2) binds to SECIS elements located in the 3¢-untranslated region of eukaryotic selenoprotein mRNAs. Selenoproteins contain the rare amino acid selenocysteine (Sec). Mutations in SECISBP2 in humans lead to reduced selenoprotein expression thereby affecting thyroid hormone-dependent growth and differentiation processes. The most severe cases also display myopathy, hearing impairment, male infertility, increased photosensitivity, mental retardation, and ataxia. Mouse models are needed to understand selenoprotein-dependent processes underlying the patients' pleiotropic phenotypes. Results: Unlike tRNA [Ser]Sec -deficient embryos, homozygous Secisbp2-deleted embryos implant, but fail before gastrulation. Heterozygous inactivation of Secisbp2 reduced the amount of selenoprotein expressed, but did not affect the thyroid hormone axis or growth. Conditional deletion of Secisbp2 in hepatocytes significantly decreased selenoprotein expression. Unexpectedly, the loss of Secisbp2 reduced the abundance of many, but not all, selenoprotein mRNAs. Transcript-specific and gender-selective effects on selenoprotein mRNA abundance were greater in Secisbp2-deficient hepatocytes than in tRNA [Ser]Sec -deficient cells. Despite the massive reduction of Dio1 and Sepp1 mRNAs, significantly more corresponding protein was detected in primary hepatocytes lacking Secisbp2 than in cells lacking tRNA [Ser]Sec . Regarding selenoprotein expression, compensatory nuclear factor, erythroid-derived, like 2 (Nrf2)-dependent gene expression, or embryonic development, phenotypes were always milder in Secisbp2-deficient than in tRNA [Ser]Sec -deficient mice. Innovation: We report the first Secisbp2 mutant mouse models. The conditional mutants provide a model for analyzing Secisbp2 function in organs not accessible in patients. Conclusion: In hepatocyte-specific conditional mouse models, Secisbp2 gene inactivation is less detrimental than tRNA [Ser]Sec inactivation. A role of Secisbp2 in stabilizing selenoprotein mRNAs in vivo was uncovered. Antioxid. Redox Signal. 21, 835-849.

Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis

“…Hence, the specific loss of PV + interneurons limits the overall survival of homozygous Gpx4 cys/cys mice due to the development of epileptic seizures. Consistent with the importance of Se for PV + interneurons, mice carrying a neuron-specific knockout in the selenoprotein biosynthesis factor Secisbp2 express very low levels of Seccontaining GPX4, present significantly reduced numbers of PV + and glutamic acid decarboxylase-67 (Gad67)-positive interneurons, and die at about the same age as Gpx4 cys/cys mice (Seeher et al, 2014). Earlier reports have already provided a link between Se status and seizures in man (Ramaekers et al, 1994;Weber et al, 1991), as well as in animal models using Se-deprived rats or conditional knockout for Trsp, SelenoP, and Gpx4 in mice (Renko et al, 2008;Savaskan et al, 2003;Wirth et al, 2010).…”

Selenium and GPX4, a vital symbiosis

“…The discrepancies in phenotypes observed for these patients is mostly accredited to different types of mutations [4]. Mouse studies using Secisbp2 deficient animals uncovered its essential function during embryogenesis suggesting that the point mutations observed in patients affect specific functions of SECISBP2 by generating hypomorphic variants [26]. a) SEPSECS Mutations in SEPSECS have been initially characterized in nonconsanguineous Sephardic Jewish families of Moroccan or Iraqi ancestry [27,28].…”

Characterization of the UGA-recoding and SECIS-binding activities of SECIS-binding protein 2

“…[17][18][19][20][21] In general, affected patients usually have a combination of heterozygous mutations that are not completely functionally null, resulting in a partial SBP2 deficiency. This is not surprising given that the mouse knockout model of SBP2 is embryonically lethal, 22 as are several selenoprotein knockouts 23,24 supporting the essential nature of some selenoproteins. The most common clinical phenotype is an unusual thyroid hormone profile, as the deiodinase proteins, which are integral to thyroid hormone signaling, are selenoproteins.…”