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

作者：Katsuki Mukaigasa, Tadayuki Tsujita, Vu Thanh Nguyen, Li Li, Hirokazu Yagi, Yuji Fuse, Yaeko Nakajima‐Takagi, Koichi Kato, Masayuki Yamamoto, Makoto Kobayashi · 发表于：Proceedings of the National Academy of Sciences · 年份：2018 · DOI：10.1073/pnas.1714056115 · 被引用次数：66 · 研究领域：Endoplasmic Reticulum Stress and Disease、Autophagy in Disease and Therapy、Genomics, phytochemicals, and oxidative stress

Significance Nrf2 is a master regulator of the antioxidant response and xenobiotic metabolism. In this paper, we demonstrate that Nrf2 also plays a critical role in the endoplasmic reticulum (ER) stress response using a zebrafish mutant in which Nrf2 is spontaneously activated. The gene responsible for this mutant was phosphomannomutase 2 ( pmm2 ), the enzyme required for the N-glycosylation. Human PMM2 is known to be the gene responsible for PMM2-CDG (congenital disorders of glycosylation), which currently has no therapeutic options. pmm2 mutant larvae showed up-regulated ER stress and ER stress-dependent Nrf2 activation. Of note, the ER stress in mutant larvae was attenuated following treatment with the Nrf2 activator sulforaphane, suggesting that the pathological conditions of ER stress-associated diseases may be improved by taking Nrf2-activating foods.