Nrf2 and selenoproteins are essential for maintaining oxidative homeostasis in erythrocytes and protecting against hemolytic anemia.

Reactive oxygen species (ROS) are highly destructive toward cellular macromolecules. However, moderate levels of ROS can contribute to normal cellular processes including signaling. Herein we evaluate the consequence of a pro-oxidant environment on hematopoietic homeostasis. The NF-E2 related factor 2 (Nrf2) transcription factor regulates genes related to ROS scavenging and detoxification. Nrf2 responds to altered cellular redox status, such as occurs with loss of antioxidant selenoproteins after deletion of the selenocysteine-tRNA gene (Trsp). Conditional knockout of the Trsp gene using Mx1-inducible Cre-recombinase leads to selenoprotein deficiency and anemia on a wild-type background, whereas Trsp:Nrf2 double deficiency dramatically exacerbates the anemia and increases intracellular hydrogen peroxide levels in erythroblasts. Results indicate that Nrf2 compensates for defective ROS scavenging when selenoproteins are lost from erythroid cells. We also observed thymus atrophy in single Trsp-conditional knockout mice, suggesting a requirement for selenoprotein function in T-cell differentiation within the thymus. Surprisingly, no changes were observed in the myelomonocytic or megakaryocytic populations. Therefore, our results show that selenoprotein activity and the Nrf2 gene battery are particularly important for oxidative homeostasis in erythrocytes and for the prevention of hemolytic anemia.