Li Jiang, Du Xingrong, Shi Hao, Deng Kejing, Chi Hongbo, Tao Wufan
the Obstetrics and Gynecology Hospital and Institute of Reproduction and Development, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai 200011, China, and From the Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China.
From the Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China, the Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
J Biol Chem. 2015 Dec 25;290(52):30762-70. doi: 10.1074/jbc.M115.668442. Epub 2015 Nov 3.
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.
调节性T细胞（Tregs）在维持免疫耐受中发挥着关键作用。转录因子Foxp3是Treg发育和功能的关键调节因子，其表达在转录和翻译后水平均受到调控。赖氨酸乙酰转移酶/赖氨酸去乙酰化酶介导的乙酰化是Foxp3主要的翻译后修饰之一，可调节Foxp3的稳定性和转录活性。然而，在Treg发育和Treg功能维持过程中，这些赖氨酸乙酰转移酶/赖氨酸去乙酰化酶的活性是如何被调节以保持适当的Foxp3乙酰化的机制仍有待确定。在此，我们报告Mst1可通过在翻译后水平调节Foxp3蛋白来增强Foxp3的稳定性、转录活性及Treg功能。我们发现Mst1可通过抑制Sirt1活性来增加Foxp3的乙酰化，这需要Mst1的激酶活性。我们还发现Mst1可通过直接与Foxp3相互作用，阻止或干扰Sirt1与Foxp3之间的相互作用，从而减弱Sirt1介导的Foxp3去乙酰化。因此，Mst1可通过激酶依赖和激酶非依赖的方式调节Foxp3的稳定性。最后，我们表明用Sirt1特异性抑制剂Ex-527处理Mst1基因敲除（-/-）的Tregs可部分恢复其抑制功能。我们的研究揭示了一种新机制，即Mst1在翻译后水平增强Foxp3表达和Treg功能。
