Analyses of Fruit Flies That Do Not Express Selenoproteins or Express the Mouse Selenoprotein, Methionine Sulfoxide Reductase B1, Reveal a Role of Selenoproteins in Stress Resistance

Abstract

Selenoproteins are essential in vertebrates because of their crucial role in cellular redox homeostasis, but some invertebrates that lack selenoproteins have recently been identified. Genetic disruption of selenoprotein biosynthesis had no effect on lifespan and oxidative stress resistance of Drosophila melanogaster. In the current study, fruit flies with knock-out of the selenocysteine-specific elongation factor were metabolically labeled with 75 Se; they did not incorporate selenium into proteins and had the same lifespan on a chemically defined diet with or without selenium supplementation. These flies were, however, more susceptible to starvation than controls, and this effect could be ascribed to the function of selenoprotein K. We further expressed mouse methionine sulfoxide reductase B1 (MsrB1), a selenoenzyme that catalyzes the reduction of oxidized methionine residues and has protein repair function, in the whole body or the nervous system of fruit flies. This exogenous selenoprotein could only be expressed when the Drosophila selenocysteine insertion sequence element was used, whereas the corresponding mouse element did not support selenoprotein synthesis. Ectopic expression of MsrB1 in the nervous system led to an increase in the resistance against oxidative stress and starvation, but did not affect lifespan and reproduction, whereas ubiquitous MsrB1 expression had no effect. Dietary selenium did not influence lifespan of MsrB1-expressing flies. Thus, in contrast to vertebrates, fruit flies preserve only three selenoproteins, which are not essential and play a role only under certain stress conditions, thereby limiting the use of the micronutrient selenium by these organisms. Selenium is an important dietary micronutrient in mammals.The major biological form of selenium is the non-canonical amino acid, selenocysteine (Sec).2 The majority of selenoproteins with known type of catalytic activity act as oxidoreductases that use Sec directly for catalysis and maintenance of cellular redox homeostasis. The number of selenoproteins in eukaryotic organisms varies significantly. Higher plants and fungi lack selenoprotein genes, whereas there are many such genes in algae and vertebrates, e.g. 10 -57 in algae, 30 -37 in fish, and 23-25 in mammals (1). At least five mammalian selenoproteins are essential (2-4). Remarkably, insects possess cysteinecontaining homologs or lack all essential mammalian selenoproteins, e.g. thioredoxin reductases and glutathione peroxidases. Moreover, recent studies identified five species of selenoproteinless insects, including the red flour beetle Tribolium castaneum (5), the silkworm Bombyx mori (5), the fly Drosophila willistoni (6), the honey bee Apis mellifera (6), and the wasp Nasonia vitripennis (6). This evolutionary reduction in the use of selenoproteins could be associated with considerable changes in antioxidant defense systems of insects (7-9).The Sec incorporation machinery is conserved across eukaryotes. Sec is encoded by the UGA codon that usually serves as a terminatio...

Methionine Sulfoxide Reductases Preferentially Reduce Unfolded Oxidized Proteins and Protect Cells from Oxidative Protein Unfolding

“…MSRs, which repair oxidative modifications, play important roles in the protection of proteins from oxidative stress in various eukaryotes (12)(13)(14). Similar protective effects were also observed in prokaryotes, particularly in the case of the stress induced by hypochlorite, a strong antimicrobial agent found in household bleach that is also produced by mammalian neutrophils to kill invading microorganisms (15).…”

Transcriptional activation of antioxidants may compensate for selenoprotein deficiencies in Amblyomma maculatum (Acari: Ixodidae) injected with selK‐ or selM‐dsRNA

“…The number of selenoproteins varies widely, from 10–57 in algae, 30–37 in fish, and 23–25 in mammals, but are not universal, particularly so in arthropods (Lobanov et al 2009; Mariotti et al 2012). Some insect species possess cysteine-containing homologs or may lack selenoproteins altogether, such as thioredoxin reductase and glutathione peroxidases, which are essential in mammalian systems (Shchedrina et al 2011b). The reduction in selenoproteins can in part be attributed to the simplicity in the conversion of a Sec to a Cys codon, which requires only a single point mutation (Mariotti et al 2012).…”

Methionine sulfoxide reductase B1 deficiency does not increase high-fat diet-induced insulin resistance in mice

“…MsrA deficiency results in increased oxidation of insulin receptor in skeletal muscle, and thus, reduces receptor function. However, although MsrB1 plays a protective role against oxidative stress in transgenic flies and mammalian cells [28,29], no significantly greater accumulation of oxidative stress was observed in the skeletal muscles or livers of chow-fed MsrB1 knockout mice than in chow-fed wild-type mice. In addition, MsrB1 deficiency had no effect on the high-fat diet-induced oxidative stress in these tissues.…”