Abstract
Selenocysteine is inserted into selenoproteins via the translational recoding of a UGA codon, normally used as a stop signal. This process depends on the nature of the selenocysteine insertion sequence element located in the 3' UTR of selenoprotein mRNAs, selenium bioavailability, and, possibly, exogenous stimuli. To further understand the function and regulation of selenoproteins in antioxidant defense and redox homeostasis, we investigated how oxidative stress influences selenoprotein expression as a function of different selenium concentrations. We found that selenium supplementation of the culture media, which resulted in a hierarchical up-regulation of selenoproteins, protected HEK293 cells from reactive oxygen species formation. Furthermore, in response to oxidative stress, we identified a selective up-regulation of several selenoproteins involved in antioxidant defense (Gpx1, Gpx4, TR1, SelS, SelK, and Sps2). Interestingly, the response was more efficient when selenium was limiting. Although a modest change in mRNA levels was noted, we identified a novel translational control mechanism stimulated by oxidative stress that is characterized by up-regulation of UGA-selenocysteine recoding efficiency and relocalization of SBP2, selenocysteine-specific elongation factor, and L30 recoding factors from the cytoplasm to the nucleus.
Highlights
Selenoproteins are important enzymes involved in antioxidant defense, redox homeostasis, and signaling
We found that selenium supplementation of the culture media, which resulted in a hierarchical up-regulation of selenoproteins, protected HEK293 cells from reactive oxygen species formation
A modest change in mRNA levels was noted, we identified a novel translational control mechanism stimulated by oxidative stress that is characterized by up-regulation of UGA-selenocysteine recoding efficiency and relocalization of SBP2, selenocysteine-specific elongation factor, and L30 recoding factors from the cytoplasm to the nucleus
Summary
Selenoproteins are important enzymes involved in antioxidant defense, redox homeostasis, and signaling. Many studies have shown that selenium levels differentially control the expression of the selenoproteome in mammals and cultured cells This regulation occurs moderately at the level of mRNA transcription/stability, but mostly during translation, to maintain essential selenoproteins at the expense of the others (18 –21). ROS induce a rapid activation of the NRF2 and NF-B transcription factors [29] Their targets include a multitude of genes involved in the stress response, antioxidant activity, the anti-inflammatory response, DNA repair, molecular chaperones, proteasome systems, and two selenoproteins, Gpx (mostly expressed in the intestine) and TR1 (an essential cytoplasmic enzyme). We investigated the regulation of selenoprotein expression in the context of H2O2-induced oxidative stress as a function of selenium concentration in the culture media, defined as control (Ctrl) and supplemented (Sup) conditions. We determined that H2O2-induced up-regulation of selenoproteins is due to a novel translational control mechanism leading to the stimulation of UGA recoding efficiency in selenoprotein mRNAs
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