Priebs, Josephine, Ridolfi, Verena Alexia, Philipp, Thilo Magnus, Kohnlein, Karl, Klotz, Lars-Oliver, Steinbrenner, Holger
[
International Worm Meeting,
2021]
The C. elegans ortholog of human selenium-binding protein 1 (SELENBP1), Y37A1B.5, is a pro-aging factor that confers resistance to high doses of selenite (1). SELENBP1 was recently identified as a methanethiol oxidase (MTO), catalyzing the conversion of methanethiol to hydrogen sulfide (H2S), hydrogen peroxide (H2O2) and formaldehyde. Here, we tested whether Y37A1B.5 has MTO activity and whether the AMPK orthologs AAK-1/-2 are involved in the effects of the protein on C. elegans lifespan. We developed an MTO activity assay that is based on in situ-generation of methanethiol from methionine as catalyzed by a bacterial recombinant L-methionine gamma-lyase, followed by detection of two methanethiol oxidation products, H2S and H2O2. Using this assay, we demonstrate MTO activity of isolated recombinant Y37A1B.5, similar to recombinant human SELENBP1. Moreover, MTO activity was detected in lysates from wild-type nematodes but not in lysates from a newly generated Y37A1B.5-deficient mutant strain, suggesting that the Y37A1B.5 protein is the major C. elegans MTO. Thus, Y37A1B.5 was named SEMO-1 (SELENBP1 ortholog with MTO activity). It is a novel methanethiol oxidase and therefore a novel potential source of H2S and H2O2, two molecules known to affect lifespan in C. elegans. A Y37A1B.5/SEMO-1-deficient mutant strain showed an extended lifespan similar to the previously reported worms exposed to Y37A1B.5-specific RNAi (1). SEMO-1, therefore, is a factor apparently shortening C. elegans lifespan. Interestingly, lifespan extension following SEMO-1 depletion was abrogated in an AAK-deficient strain (NB245; deficient in both isoforms of the catalytic AAK subunit), and vice versa, SEMO-1 depletion through RNAi appeared to enhance AAK phosphorylation in wild-type worms. As AAK activity is known to be related to C. elegans lifespan, we propose that the extended lifespan of SEMO-1-depleted worms is caused by AAK activation. The mode of AAK activation following SEMO-1 depletion remains to be identified. (1) Kohnlein K, Urban N, Guerrero-Gomez D, Steinbrenner H, Urbánek P, Priebs J, Koch P, Kaether C, Miranda-Vizuete A, Klotz LO. Redox Biol. 28:101323 (2020).