Phosphorylation of tyrosine 568 controls nuclear export of Nrf2

Nuclear factor Nrf2, under normal conditions, is retained in the cytosol by INrf2. Antioxidants and oxidants antagonize this interaction, resulting in the release of Nrf2. Nrf2 translocates to the nucleus binds to ARE and activates a battery of chemopreventive genes. Once this is achieved, Nrf2 is exported out of the nucleus, binds with INrf2, and degrades. Nrf2 contains well defined signals that control nuclear import and export of Nrf2. The present studies demonstrate that phosphorylation of tyrosine 568 is required for Crm1-mediated nuclear export and degradation of Nrf2. Mutation of tyrosine 568 to alanine and phenylalanine resulted in the loss of interaction with Crm1 and abrogation of nuclear export of Nrf2. Nrf2Y568A is deficient in nuclear export and displays delayed degradation compared with wild-type Nrf2. In addition, Src inhibitor PP2 caused nuclear accumulation of Nrf2 in normal and hydrogen peroxide-treated cells but had no effect on localization of mutant Nrf2Y568A. Further experiments with small interfering RNA revealed that Fyn phosphorylated Nrf2Y568 leading to nuclear export and degradation of Nrf2.