Abstract
Regulatory T cells (Tregs) play crucial roles in maintaining immune tolerance. The transcription factor Foxp3 is a critical regulator of Treg development and function, and its expression is regulated at both transcriptional and post-translational levels. Acetylation by lysine acetyl transferases/lysine deacetylases is one of the main post-translational modifications of Foxp3, which regulate Foxp3's stability and transcriptional activity. However, the mechanism(s) by which the activities of these lysine acetyl transferases/lysine deacetylases are regulated to preserve proper Foxp3 acetylation during Treg development and maintenance of Treg function remains to be determined. Here we report that Mst1 can enhance Foxp3 stability, its transcriptional activity, and Treg function by modulating the Foxp3 protein at the post-translational level. We discovered that Mst1 could increase the acetylation of Foxp3 by inhibiting Sirt1 activity, which requires the Mst1 kinase activity. We also found that Mst1 could attenuate Sirt1-mediated deacetylation of Foxp3 through directly interacting with Foxp3 to prevent or interfere the interaction between Sirt1 and Foxp3. Therefore, Mst1 can regulate Foxp3 stability in kinase-dependent and kinase-independent manners. Finally, we showed that treatment of Mst1(-/-) Tregs with Ex-527, a Sirt1-specific inhibitor, partially restored the suppressive function of Mst1(-/-) Tregs. Our studies reveal a novel mechanism by which Mst1 enhances Foxp3 expression and Treg function at the post-translational level.
Highlights
Post-translational modifications such as acetylation, phosphorylation, and ubiquitination have been demonstrated to regulate protein stability and activity
We found that the GFP-Foxp3 fusion protein was located in 100% of nuclei of both WT and Mst1Ϫ/Ϫ MEFs (Fig. 1E), indicating that Mst1 deficiency does not affect the subcellular localization of the Foxp3 protein
Because maintenance of Foxp3 output is crucial for Treg cell-mediated immunosuppression, Foxp3 expression is tightly controlled at the transcriptional level by multiple signaling pathways [42,43,44,45,46]
Summary
Post-translational modifications such as acetylation, phosphorylation, and ubiquitination have been demonstrated to regulate protein stability and activity. We report that Mst1 can enhance Foxp3 stability, its transcriptional activity, and Treg function by modulating the Foxp3 protein at the post-translational level. Our studies reveal a novel mechanism by which Mst1 enhances Foxp3 expression and Treg function at the post-translational level.
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