PIM1 kinase phosphorylates the human transcription factor FOXP3 at serine 422 to negatively regulate its activity under inflammation [Gene Regulation]

August 5th, 2014 by Li, Z., Lin, F., Zhuo, C., Deng, G., Chen, Z., Yin, S., Gao, Z., Piccioni, M., Tsun, A., Cai, S., Zheng, S. G., Zhang, Y., Li, B.

Previous reports have suggested that human CD4+CD25hiFOXP3+ T regulatory cells (Tregs) have functional plasticity and may differentiate into effector T cells under inflammation. The molecular mechanisms underlying these findings remain unclear. Here, we identified residue S422 of human FOXP3 as a phosphorylation site that regulates its function, which is not present in murine Foxp3. PIM1 kinase, which is highly expressed in human Tregs, was found able to interact with and to phosphorylate human FOXP3 at S422. TCR signaling inhibits PIM1 induction, while IL-6 promotes PIM1 expression in in vitro expanded human Tregs. PIM1 negatively regulates FOXP3 chromatin binding activity by specifically phosphorylating FOXP3 at S422. Our data also suggest that phosphorylation of FOXP3 at Ser418 site could prevent FOXP3 phosphorylation at S422 mediated by PIM1. Knockdown of PIM1 in in vitro expanded human Tregs promoted FOXP3-induced target genes expression, including CD25, CTLA4 and GITR, or weaken FOXP3-suppressed gene IL-2 expression, and enhanced immunosuppressive activity of Treg cells. Furthermore, PIM1-specific inhibitor boosted FOXP3 DNA binding activity in in vitro expanded primary Treg cells and also enhanced their suppressive activity towards the proliferation of T effector cells. Taken together, our findings suggest that PIM1 could be a new potential therapeutic target in the prevention and treatment of human specific autoimmune diseases due to its ability to modulate the immunosuppressive activity of human Tregs.
  • Posted in Journal of Biological Chemistry, Publications
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