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. Zfat (zinc-finger protein in autoimmune thyroid disease susceptibility region/zinc-finger protein with AT-hook) is a nuclear protein that harbours an AT-hook domain and 18- repeats of the C2H2 zinc-finger motif of which amino acid sequences are highly conserved from fishes to higher