Abstract
Human selenium-binding protein 1 (SELENBP1) was originally identified as a protein binding selenium, most likely as selenite. SELENBP1 is associated with cellular redox and thiol homeostasis in several respects, including its established role as a methanethiol oxidase that is involved in degradation of methanethiol, a methionine catabolite, generating hydrogen sulfide (H2S) and hydrogen peroxide (H2O2). As both H2S and reactive oxygen species (such as H2O2) are major regulators of Caenorhabditis elegans lifespan and stress resistance, we hypothesized that a SELENBP1 ortholog in C. elegans would likely be involved in regulating these aspects.Here we characterize Y37A1B.5, a putative selenium-binding protein 1 ortholog in C. elegans with 52% primary structure identity to human SELENBP1. While conferring resistance to toxic concentrations of selenite, Y37A1B.5 also attenuates resistance to oxidative stress and lowers C. elegans lifespan: knockdown of Y37A1B.5 using RNA interference resulted in an approx. 10% increase of C. elegans lifespan and an enhanced resistance against the redox cycler paraquat, as well as enhanced motility. Analyses of transgenic reporter strains suggest hypodermal expression and cytoplasmic localization of Y37A1B.5, whose expression decreases with worm age. We identify the transcriptional coregulator MDT-15 and transcription factor EGL-27 as regulators of Y37A1B.5 levels and show that the lifespan extending effect elicited by downregulation of Y37A1B.5 is independent of known MDT-15 interacting factors, such as DAF-16 and NHR-49. In summary, Y37A1B.5 is an ortholog of SELENBP1 that shortens C. elegans lifespan and lowers resistance against oxidative stress, while allowing for a better survival under toxic selenite concentrations.
Highlights
Selenium (Se) is an essential trace element for humans and animals that is biologically active mostly in the form of selenocysteine built into selenoproteins
The human selenoproteome consists of 25 selenoproteins and includes five glutathione peroxidase (GPx), one methionine sulfoxide reductase (Msr) and three thioredoxin reductase (TrxR) isoform(s), which are involved in the removal of reactive oxygen species (ROS) such as hydroperoxides, the repair of oxidized methionine residues in proteins and the maintenance of cellular and systemic redox homeostasis [1,2,3]
Y37A1B.5, a protein hitherto uncharacterized, is a C. elegans ortholog of SELENBP1 that allows for a better survival of nematodes exposed to toxic selenite concentrations, while it is dispensable for adult worms grown under standard laboratory conditions
Summary
Selenium (Se) is an essential trace element for humans and animals that is biologically active mostly in the form of selenocysteine built into selenoproteins. C. elegans expresses a functional machinery allowing for incorporation of selenocysteine into this single protein, deletion of the trxr-1 gene does not shorten C. elegans lifespan [7], and does not affect sensitivity of C. elegans towards toxic effects of inorganic Se compounds on survival, growth and development [8,9]. Two further types of Secontaining proteins were described in mammalian cells: those that have non- incorporated selenomethionine instead of methionine and the small group of selenium-binding proteins [10]. Some associations with (patho-)physiological processes were described, including a link to cell differentiation [12,13] and a correlation between low SELENBP1 expression levels in tumor tissue and poor clinical outcome Some associations with (patho-)physiological processes were described, including a link to cell differentiation [12,13] and a correlation between low SELENBP1 expression levels in tumor tissue and poor clinical outcome (for review, see Ref. [14])
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