Model for the effect of Nrf2 and selenoprotein loss on hematopoietic cells. (A) Under normal conditions, selenoproteins maintain redox balance while the Nrf2 gene battery is repressed by Kelch-like ECH-associated protein–mediated proteasomal degradation. (B) Therefore, in the steady state, oxidative homeostasis is maintained even in the absence of Nrf2. (C) In the case of a pro-oxidant environment, created in blood by disrupting selenoprotein synthesis, Nrf2 is activated and helps maintain homeostasis in immature erythrocytes. However, Nrf2 cannot fully compensate for loss of the selenoproteins-mediated antioxidant machinery, especially in mature erythrocytes, and therefore mice lacking selenoprotein activity suffer from mild anemia. On the other hand, the impairment seen in lymphocytes is ROS independent. (D) Since selenoprotein activities and the Nrf2 gene battery co-operatively maintain the oxidative homeostasis of immature erythrocytes, combined disruption of these 2 antioxidant systems leads to severe anemia. Ig, immunoglobulin.