A Caenorhabditis elegans ortholog of human selenium-binding protein 1 is a pro-aging factor protecting against selenite toxicity

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.

Interrelation between ROS and Ca2+ in aging and age-related diseases

“…Although their characteristics are entirely different, they are both in crucial positions to modulate the process of aging [ 8 ]. For instance, lifespan and stress resistance of Caenorhabditis elegans ( C. elegans ) are also strongly dependent on redox and thiol homeostasis [ 9 ] as well as cellular Ca 2+ homeostasis [ 10 ]. In turn, the process of aging causes alterations in ROS and Ca 2+ homeostasis too.…”

Control of clathrin-mediated endocytosis by NIMA family kinases

“…Single copy miniMos transgenes were generated to express markers for plasma membrane clathrin-coated pits (DPY-23/APM-2/μ2) and Trans-Golgi Network clathrin-coated pits (APM-1/μ1) in the hypodermis [113]. Genomic DNA for apm-1, and a published minigene for dpy-23, was cloned into a customized version of miniMos vector pCFJ910, including the hyp7-specific promoter from gene Y37A1B.5 (P hyp7 ), red fluorescent protein wrmScarlet-I (mScarlet), and the 3'UTR from gene let-858 [40,114,115].…”

A coupled enzyme assay for detection of selenium-binding protein 1 (SELENBP1) methanethiol oxidase (MTO) activity in mature enterocytes

“…Selenium, on the other hand, appears to bind to SELENBP1 mainly if applied at non-physiologically high doses [ 24 ]. Thus, SELENBP1 might provide an intracellular selenium buffer to cope with cytotoxic effects of selenite, as proposed for the C. elegans ortholog [ 25 , 26 ] rather than being dependent on selenium for its MTO activity. This idea is supported by a report showing SELENBP1 induction in human gastric cancer cells that were exposed to a cytotoxic dose of 30 μM selenite [ 27 ], whereas an adequate dose of 100 nM selenite did not result in elevated SELENBP1 levels in murine 3T3-L1 adipocytes [ 12 ].…”

“…Similarly, Selenbp1-deficient mice also displayed no major phenotypical differences as compared to wild-type mice [ 5 , 28 ]. Gly-225 is evolutionarily conserved throughout all putative SELENBP1 orthologs, while His-329 is conserved only in eukaryotes [ 5 , 25 ].…”