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Molecular Pathways Associated With Methylmercury-Induced Nrf2 Modulation

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Review

Molecular Pathways Associated With Methylmercury-Induced Nrf2 Modulation

Takamitsu Unoki et al. Front Genet.

Abstract

Methylmercury (MeHg) is a potent neurotoxin that affects particularly the developing brain. Since MeHg is a potent electrophilic agent, a wide range of intracellular effects occur in response to its exposure. Yet, the molecular mechanisms associated with MeHg-induced cell toxicity have yet to be fully understood. Activation of cell defense mechanisms in response to metal exposure, including the up-regulation of Nrf2- (nuclear factor erythroid 2-related factor 2)-related genes has been previously shown. Nrf2 is a key regulator of cellular defenses against oxidative, electrophilic and environmental stress, regulating the expression of antioxidant proteins, phase-II xenobiotic detoxifying enzymes as well phase-III xenobiotic transporters. Analogous to other electrophiles, MeHg activates Nrf2 through modification of its repressor Keap1 (Kelch-like ECH-associated protein 1). However, recent findings have also revealed that Keap1-independent signal pathways might contribute to MeHg-induced Nrf2 activation and cytoprotective responses against MeHg exposure. These include, Akt phosphorylation (Akt/GSK-3β/Fyn-mediated Nrf2 activation pathway), activation of the PTEN/Akt/CREB pathway and MAPK-induced autophagy and p62 expression. In this review, we summarize the state-of-the-art knowledge regarding Nrf2 up-regulation in response to MeHg exposure, highlighting the modulation of signaling pathways related to Nrf2 activation. The study of these mechanisms is important in evaluating MeHg toxicity in humans, and can contribute to the identification of the molecular mechanisms associated with MeHg exposure.

Keywords: Nrf2; central nervous system; gene expression; methylmercury; toxicity.

Figures

FIGURE 1
FIGURE 1
Signal orchestration against MeHg toxicity. (A) Under non-stressed conditions, Nrf2 is captured by Keap1 and ubiquitinated by Cul3 in the cytosol that leads to degradation through ubiquitin–proteasome system, resulting in the inhibition of Nrf2 translocation from the cytoplasm to nucleus. Fyn is phosphorylated by GSK-3β, leading to Fyn nuclear localization. Fyn phosphorylates nuclear Nrf2, which leads to nuclear export and degradation of Nrf2. Sp1 is a transcription factor of Fyn. Steady state level of p62 and LC3-II expression under basal activity of JNK and ERK. (B) Cellular protective responses to MeHg. MeHg covalently modifies Keap1 through Cys151 and/or Cys319, leading to inhibition of Nrf2 degradation. As a result, Nrf2 translocates into nucleus and the interacts with a partner protein sMaf, resulting in formation of heterodimer that binds to the antioxidant response element (ARE), thereby upregulating its downstream genes (e.g., HO-1, GCL, and MRP) (1). MeHg induces phosphorylation of GSK-3β at Ser9 mediated by activated Akt at Thr308. Since this inactive form of GSK-3β is unable to phosphorylate Fyn, substantial retain of nuclear Nrf2 coupled to diminished nuclear translocation of Fyn occurs (2). MeHg covalently modifies PTEN, resulting in inhibition of its catalytic activity, thereby phosphorylating Akt through Thr473 and tits downstream transcription factor CREB, which binds to the cAMP-response element (CRE), leading to up-regulation of anti-apoptotic protein Bcl-2 (3). MeHg reduces Sp1 protein level and thus down-regulates Sp1-dependent target genes such as fyn (4). Phosphorylation of JNK and ERK mediated by MeHg increases p62 and LC3-II expressions, thereby promotes autophagosomal degradation of misfolded/damaged proteins (5). Possible linkage between MeHg-induced MAPK activation and Nrf2 upregulation via p62/LC3-II-mediated autophagosomal degradation of Keap1 (6). Dotted gray lines indicate processes disrupted by MeHg exposure.

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