Nrf2 activation attenuates genetic endoplasmic reticulum stress induced by a mutation in the phosphomannomutase 2 gene in zebrafish

Proceedings of the National Academy of Sciences of the United States of America
Katsuki MukaigasaMakoto Kobayashi

Abstract

Nrf2 plays critical roles in animals' defense against electrophiles and oxidative stress by orchestrating the induction of cytoprotective genes. We previously isolated the zebrafish mutant it768, which displays up-regulated expression of Nrf2 target genes in an uninduced state. In this paper, we determine that the gene responsible for it768 was the zebrafish homolog of phosphomannomutase 2 (Pmm2), which is a key enzyme in the initial steps of N-glycosylation, and its mutation in humans leads to PMM2-CDG (congenital disorders of glycosylation), the most frequent type of CDG. The pmm2 it768 larvae exhibited mild defects in N-glycosylation, indicating that the pmm2 it768 mutation is a hypomorph, as in human PMM2-CDG patients. A gene expression analysis showed that pmm2 it768 larvae display up-regulation of endoplasmic reticulum (ER) stress, suggesting that the activation of Nrf2 was induced by the ER stress. Indeed, the treatment with the ER stress-inducing compounds up-regulated the gstp1 expression in an Nrf2-dependent manner. Furthermore, the up-regulation of gstp1 by the pmm2 inactivation was diminished by knocking down or out double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK), one of the main ER stres...Continue Reading

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Citations

Jul 12, 2019·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Ciro MenaleCristina Sobacchi
Oct 20, 2019·The Journal of Biological Chemistry·Pengfei LiuAikseng Ooi
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Jun 3, 2021·Biology·Katsuya IuchiHisashi Hisatomi
Nov 17, 2021·JCI Insight·Elsenoor J KlaverHeather Flanagan-Steet

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