Abstract
Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the master regulator of the antioxidant response, and its function is tightly regulated at the transcriptional, translational, and post-translational levels. It is well-known that Nrf2 is regulated at the protein level by proteasomal degradation via Kelch-like ECH-associated protein 1 (Keap1), but how Nrf2 is regulated at the translational level is less clear. Here, we show that pharmacological stimulation increases Nrf2 levels by overcoming basal translational repression. We developed a novel reporter assay that enabled identification of natural compounds that induce Nrf2 translation by a mechanism independent of Keap1-mediated degradation. Apigenin, resveratrol, and piceatannol all induced Nrf2 translation. More importantly, the pharmacologically induced Nrf2 overcomes Keap1 regulation, translocates to the nucleus, and activates the antioxidant response. We conclude that translational regulation controls physiological levels of Nrf2, and this can be modulated by apigenin, resveratrol, and piceatannol. Also, targeting this mechanism with novel compounds could provide new insights into prevention and treatment of multiple diseases in which oxidative stress plays a significant role.
Highlights
Nuclear factor-like 2 (Nrf2) is the master regulator of the antioxidant response, and its function is tightly regulated at the transcriptional, translational, and posttranslational levels
This construct used a stop codon between the two sequences to demonstrate that the inhibition of GFP translation is mediated by the mRNA sequence of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and not by the amino acids encoded by the sequence [18]
We found that the Nrf2 regulatory element inhibits more than 70% of the expression of luciferase (Fig. 1B) and confirmed that this finding was not due to reduced levels of the Luc2–Sg3 mRNA transcript (Fig. 1C)
Summary
Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the master regulator of the antioxidant response, and its function is tightly regulated at the transcriptional, translational, and posttranslational levels. We conclude that translational regulation controls physiological levels of Nrf, and this can be modulated by apigenin, resveratrol, and piceatannol Targeting this mechanism with novel compounds could provide new insights into prevention and treatment of multiple diseases in which oxidative stress plays a significant role. This antioxidant response, and its function is tightly regulated at different levels, including transcription, translation, and posttranslational control (6 –9). The translational control allows the cells to quickly respond to noxious conditions by regulating temporal and spatial translation by keeping specific mRNA molecules in a repressed state This allows their translation in response to environmental signals without requiring mRNA transcription, maturation, and nuclear export [17].
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