Th-Inducing POK Factor (ThPOK)是决定胸腺细胞向CD4 T细胞分化的重要转录因子。其在分化过渡态细胞中开始表达，通过开启CD4分化定向的基因同时关闭CD8分化定向的基因，调控DP胸腺细胞的CD4/CD8定向分化。ThPOK可以正调控自身的表达，但最后特异表达于CD4细胞，而在CD8细胞中完全不表达。这种差异表达是如何在分化过程中建立的仍然不清楚。
该项研究揭示在DP胸腺细胞向CD4或CD8分化定向过程中，ThPOK蛋白的稳定性及乙酰化修饰水平的不同是导致其最终在CD4和CD8细胞中差异表达的可能原因。在CD4细胞中，ThPOK高乙酰化而保持稳定；相反，在CD8细胞中，ThPOK低乙酰化而迅速降解。因此，ThPOK表达的正反馈可以在CD4细胞中维持，而在CD8细胞中被阻断。此外，该工作还揭示组蛋白乙酰化酶p300特异性地催化ThPOK的乙酰化修饰，并且通过竞争同一位点的泛素化修饰而增强ThPOK的稳定性。这项工作从蛋白的转录后修饰水平阐明了调控ThPOK稳定性的一种新机制，丰富了对胸腺细胞分化信号调控网络的认识。
该研究得到来自中国科学院、科技部重大科学研究计划、国家自然科学基金委、上海市科委的经费资助。
生物谷推荐英文摘要：
The Journal of Immunology, 2010, doi:10.4049/jimmunol.1001462
p300-Mediated Acetylation Stabilizes the Th-Inducing POK Factor
Min Zhang, Jiali Zhang, Jinxiu Rui, and Xiaolong Liu
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
The lineage-specifying factor Th-inducing POK (ThPOK) directs the intrathymic differentiation of CD4 T cells. Although the regulation of ThPOK at the transcription level has been extensively studied, specific posttranslational modifications regulating the activity of ThPOK have not been addressed. In this paper, we show that ThPOK is an unstable protein that is more readily degraded in CD8 T cells compared with CD4 T cells. Among the various proteins that bind ThPOK, acetyltransferase p300 specifically promotes the acetylation of ThPOK at K210, K216, and K339, outcompeting ubiquitination, thereby stabilizing the protein. In CD4 T cells, attenuation of p300-mediated acetylation promotes the degradation of ThPOK. In contrast, mutation of lysines 210, 216, and 339 to arginines stabilizes ThPOK and enhances its ability to suppress the expression of CD8 molecule and cytotoxic effectors in CD8 T cells. Our results reveal an essential role of p300-mediated acetylation in regulating the stability of ThPOK and suggest that such regulation may play a part in CD4/CD8 lineage differentiation.
