Seven in Absentia Homolog 2 (Siah2) Protein Is a Regulator of NF-E2-related Factor 2 (Nrf2)*

Abstract

Background: Nrf2 is up-regulated in response to reoxygenation after hypoxia. Results: Hypoxia suppressed Nrf2 expression and induced Siah2 expression. Knockdown of Siah2 rescued hypoxic suppression of an Nrf2 mutant that mimicked phosphorylation at serine 40 or lacked this phosphorylation site. Conclusion: Siah2 serves as a novel regulator of Nrf2. Significance: Association of Siah2 with Nrf2 causes the degradation of Nrf2 irrespective of its phosphorylation status at serine 40.

Novel Function of E3 Ubiquitin Ligase Siah2 to Regulate ROS Metabolism

“…Recent work has demonstrated that Siah2 protein is a promising therapeutic target in pathological conditions accompanied by a low level of Nrf2 expression [7,40] . The inhibition of Siah2 expression restores the decreased expression of Nrf2-inducible genes and subsequently improves symptoms.…”

“…For example, under hypoxia, Nrf2 is phosphorylated by protein kinase C (PKC), which triggers the release from Keap1. Knockdown of Siah2 rescues hypoxia-induced reduction of both Nrf2 mutants mimicking phosphorylation at Ser40 and lacking this phosphorylation site, suggesting that Siah2 contributes to the degradation of Nrf2 irrespective of its phosphorylation status [7] ( Figure 1). In addition, the knockdown of Siah2, but not Keap1, was shown to significantly attenuate the hypoglycemia-mediated reduction of Nrf2 expression [40] .…”

“…Hypoxia induces the phosphorylation of Nrf2; then Keap1-mediated degradation of Nrf2 is decreased compared with that under normoxia. In addition, hypoxiainduced Siah2 provides a dominating of Nrf2 degradation pathway stronger than over that by Keap1 under hypoxia [7] . These phenomena suggest that Siah2 is involved in ROS metabolism.…”

“…Recent studies have also suggested that NF-E2-related factor (Nrf2), which plays an important role in ROS metabolism, is negatively regulated by Siah2 under stressful conditions [7,40] . Under basal conditions, Nrf2 is a well-known substrate for Kelchlike ECH-associated protein 1 (Keap1) [6] ; however, Siah2, but not Keap1, is involved in the degradation of Nrf2 under particular conditions.…”

“…Interfering with Nrf2 down-regulation through Siah inhibition is effective to induce the expression of cytoprotective genes [7,40] , as it may have an impact on the cellular adaptive responses to oxidative stress more broadly than the inhibition of Keap1 alone.…”