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Recoding of UGA from a stop codon to selenocysteine poses a dilemma for the protein translation machinery. In eukaryotes, two factors that are crucial to this recoding process are the mRNA binding protein of the Sec insertion sequence, SBP2, and the specialized elongation factor, EFsec. We sought to determine the subcellular localization of these selenoprotein synthesis factors in mammalian cells and thus gain insight into how selenoprotein mRNAs might circumvent nonsense-mediated decay. Intriguingly, both EFsec and SBP2 localization differed depending on the cell line but significant colocalization of the two proteins was observed in cells where SBP2 levels were detectable. We identify functional nuclear localization and export signals in both proteins, demonstrate that SBP2 undergoes nucleocytoplasmic shuttling, and provide evidence that SBP2 levels and localization may influence EFsec localization. Our results suggest a mechanism for the nuclear assembly of the selenocysteine incorporation machinery that could allow selenoprotein mRNAs to circumvent nonsense-mediated decay, thus providing new insights into the mechanism of selenoprotein translation.

Selenium, an essential trace element known primarily for its antioxidant properties, exerts a diversity of functions through its presence in selenoproteins, proteins in which selenium is incorporated into the nascent polypeptide cotranslationally by means of the amino acid selenocysteine (Sec). Although the function of many selenoprotein families is unknown, the importance of selenoprotein synthesis has been clearly demonstrated in animals, in which mutations that render the cell unable to incorporate selenium into proteins result in embryonic lethality (1). With few exceptions, characterized selenoprotein families are known to function enzymatically and are typically involved in redox reactions. In these selenoprotein families, the Sec residue is found in the active site of the enzyme. Because nearly all eukaryotic selenoproteins are represented within mammalian genomes, mammals have been thought to recapitulate the eukaryotic selenoproteome, the set of all selenoproteins. However, by using bioinformatic approaches, Castellano et al. (2) have identified and characterized a fish selenoprotein family, SelJ, that challenges these paradigms. Their findings, published in this issue of PNAS, reinforce the seemingly universal importance of selenium by showing the vast and diverse phylogenetic distributions of selenoproteins across taxa. Selenoprotein translation relies on …