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bioRxiv · 10.1101/2025.01.09.632117

The transsulfuration pathway suppresses the embryonic lethalphenotype of glutathione reductase mutants in Caenorhabditis elegans

Valenzuela-Villatoro, M.·Guerrero-Gomez, D.·Gomez-Orte, E.·Cheng, Q.·Zheleva, A.·Mora-Lorca, J. A.·Petrovic, D.·O'Neil, N. J.·Ceron, J.·Hatakeyama, A.·Onami, S.·Filipovic, M.·Arner, E. S.·Cabello, J.·Miranda-Vizuete, A.
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Abstract

The gsr-1 gene encodes the only glutathione reductase in Caenorhabditis elegans and gsr-1 loss of function alleles have a fully penetrant embryonic lethal phenotype. Therefore, maintenance of glutathione redox homeostasis is essential for nematode survival. We report here that impairment of the nonsense-mediated mRNA decay (NMD) pathway suppresses the embryonic lethality of gsr-1 mutants, allowing their normal development and growth. This NMD pathway dependent suppression requires cth-1 and cth-2 that encode, respectively, two isoforms of cystathionine-{gamma}-lyase that catalyze the conversion of cystathionine to cysteine through the transsulfuration pathway. Interestingly, the thioredoxin system that can also provide cysteine through the cystine reduction pathway is not required for the suppression of the lethal phenotype of gsr-1 embryos when the NMD pathway is inactivated. Together, our data indicate that increasing the activity of the reverse transsulfuration pathway can compensate the detrimental effect of the gsr-1 mutation, raising the interesting question of why C. elegans has not preserved such compensatory mechanism to avoid the embryonic lethality of these mutants. HighlightsO_LIA novel cryptic deletion in the smg-3 gene suppresses the embryonic lethality of C. elegans gsr-1 mutants. C_LIO_LIInactivation of the nonsense-mediated mRNA decay (NMD) pathway allows survival of gsr-1 mutant worms. C_LIO_LIGenetic impairment of the transsulfuration pathway restores the embryonic lethal phenotype in gsr-1; smg-3 mutants. C_LI

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Valenzuela-Villatoro, M., Guerrero-Gomez, D., Gomez-Orte, E., Cheng, Q., Zheleva, A., Mora-Lorca, J. A., Petrovic, D., O'Neil, N. J., Ceron, J., Hatakeyama, A., Onami, S., Filipovic, M., Arner, E. S., Cabello, J., Miranda-Vizuete, A.. 2025-01-13. The transsulfuration pathway suppresses the embryonic lethalphenotype of glutathione reductase mutants in Caenorhabditis elegans. https://doi.org/10.1101/2025.01.09.632117

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