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Methylmercury augments Nrf2 activity by downregulation of the Src family kinase Fyn.

ABSTRACT: Methylmercury (MeHg) is a potent developmental neurotoxicant that induces an oxidative stress response in the brain. It has been demonstrated that MeHg exposure increases nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Nrf2 is a transcription factor that translocates to the nucleus in response to oxidative stress, and upregulates phase II detoxifying enzymes. Although, Nrf2 activity is augmented subsequent to MeHg exposure, it has yet to be established whether Nrf2 moves into the nucleus as a result. Furthermore, the potential effect MeHg might have on the non-receptor tyrosine kinase, Fyn, has not been addressed. Fyn phosphorylates Nrf2 in the nucleus, resulting in its inactivation, and consequent downregulation of the oxidative stress response. Here, we observe Nrf2 translocates to the nucleus subsequent to MeHg-induced oxidative stress. This response is concomitant with reduced Fyn expression and nuclear localization. Moreover, we detected an increase in phosphorylated Akt and glycogen synthase kinase 3 beta (GSK-3?) at activating and inhibitory sites, respectively. Akt phosphorylates and inhibits GSK-3?, which subsequently prevents Fyn phosphorylation to signal nuclear import. Our results demonstrate MeHg downregulates Fyn to maintain Nrf2 activity, and further illuminate a potential mechanism by which MeHg elicits neurotoxicity.

SUBMITTER: Culbreth M

PROVIDER: S-EPMC5623621 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Methylmercury augments Nrf2 activity by downregulation of the Src family kinase Fyn.

Culbreth Megan M Zhang Ziyan Z Aschner Michael M

Neurotoxicology 20170720

Methylmercury (MeHg) is a potent developmental neurotoxicant that induces an oxidative stress response in the brain. It has been demonstrated that MeHg exposure increases nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Nrf2 is a transcription factor that translocates to the nucleus in response to oxidative stress, and upregulates phase II detoxifying enzymes. Although, Nrf2 activity is augmented subsequent to MeHg exposure, it has yet to be established whether Nrf2 moves into the nu ...[more]

PMID: 28736149

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Project description:In perfused rat liver, hyperosmolarity induces Mrp2- (Kubitz, R., D'urso, D., Keppler, D., and Häussinger, D. (1997) Gastroenterology 113, 1438-1442) and Bsep retrieval (Schmitt, M., Kubitz, R., Lizun, S., Wettstein, M., and Häussinger, D. (2001) Hepatology 33, 509-518) from the canalicular membrane leading to cholestasis. The aim of this study was to elucidate the underlying signaling events. Hyperosmolarity-induced retrieval of Mrp2 and Bsep from the canalicular membrane in perfused rat liver was accompanied by an activating phosphorylation of the Src kinases Fyn and Yes but not of c-Src. Both hyperosmotic transporter retrieval and Src kinase activation were sensitive to apocynin (300 μmol/liter), N-acetylcysteine (NAC; 10 mmol/liter), and SU6656 (1 μmol/liter). Also PP-2 (250 nmol/liter), which inhibited hyperosmotic Fyn but not Yes activation, prevented hyperosmotic transporter retrieval from the canalicular membrane, suggesting that Fyn but not Yes mediates hyperosmotic Bsep and Mrp2 retrieval. Neither hyperosmotic Fyn activation nor Bsep/Mrp2 retrieval was observed in livers from p47(phox) knock-out mice. Hyperosmotic activation of JNKs was sensitive to apocynin and NAC but insensitive to SU6656 and PP-2, indicating that JNKs are not involved in transporter retrieval, as also evidenced by experiments using the JNK inhibitors L-JNKI-1 and SP6001255, respectively. Hyperosmotic transporter retrieval was accompanied by a NAC and Fyn knockdown-sensitive inhibition of biliary excretion of the glutathione conjugate of 1-chloro-2,4-dinitrobenzene in perfused rat liver and of cholyl-L-lysyl-fluorescein secretion into the pseudocanaliculi formed by hepatocyte couplets. Hyperosmolarity triggered an association between Fyn and cortactin and increased the amount of phosphorylated cortactin underneath the canalicular membrane. It is concluded that the hyperosmotic cholestasis is triggered by a NADPH oxidase-driven reactive oxygen species formation that mediates Fyn-dependent retrieval of the Mrp2 and Bsep from the canalicular membrane, which may involve an increased cortactin phosphorylation.

Dataset Information

Methylmercury augments Nrf2 activity by downregulation of the Src family kinase Fyn.

Publications

Methylmercury augments Nrf2 activity by downregulation of the Src family kinase Fyn.

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