Marked Reduction in FoxO1 Protein by its Enhanced Proteasomal Degradation in Zfat-deficient Peripheral T-Cells.

BACKGROUND Zfat is a nuclear protein that harbours putative DNA-binding domains. T-cell specific deletion of Zfat in Zfat(f/f)-CD4Cre mice yields a significant decrease in the number of peripheral T-cells with a lower surface expression of interleukin-7 receptor-α (IL-7Rα). However, the molecular mechanism by which Zfat controls IL-7Rα expression remains unknown. MATERIALS AND METHODS Expression levels of the molecules involved in IL-7Rα expression were determined by immunoblotting. RESULTS Zfat-deficient peripheral T-cells showed a marked reduction in the FoxO1 protein that regulates IL-7Rα expression; however, the FoxO1 mRNA expression level was not affected by Zfat-deficiency. Furthermore, treatment of Zfat-deficient T-cells with a proteasome inhibitor, epoxomicin, restored FoxO1 expression levels, indicating that the loss of Zfat enhanced the proteasomal degradation of the FoxO1 protein. CONCLUSION These results suggest that Zfat is required for peripheral T-cell homeostasis through IL-7Rα expression by controlling the FoxO1 protein.