Department of Pulmonary Medicine, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, PR China.
Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (CAS), Shanghai 200031, PR China.
Biochem Biophys Res Commun. 2014 Jul 4;449(3):289-94. doi: 10.1016/j.bbrc.2014.05.037. Epub 2014 May 17.
The T-box transcriptional factor T-bet is crucial in the development, differentiation and function of Th1 cells. It drives Th1 immune response primarily through promoting expression of Th1 hallmark cytokine IFN-γ. Although T-bet was found associated with many immune-mediated diseases such as asthma and systemic sclerosis, little is known about the regulation of T-bet stability and function. Here we identified USP10, a carboxyl-terminal ubiquitin-processing protease, could interact with T-bet in the nucleus. Overexpression of USP10 directly inhibited T-bet ubiquitination and increased the expression of T-bet. We further confirmed Quercetin, a reported inhibitor of T-bet, could target USP10. Quercetin treatment downregulated USP10 and promoted T-bet degradation in a proteasome dependent way. Moreover, we found USP10 expression was upregulated in asthmatic patient PBMC, suggesting USP10 may maintain high level of T-bet and IFN-γ to fight against Th2-dominated inflammation.
T 盒转录因子 T-bet 在 Th1 细胞的发育、分化和功能中起着至关重要的作用。它主要通过促进 Th1 标志性细胞因子 IFN-γ 的表达来驱动 Th1 免疫反应。尽管 T-bet 与许多免疫介导的疾病有关，如哮喘和系统性硬化症，但人们对 T-bet 稳定性和功能的调节知之甚少。在这里，我们鉴定了 USP10，一种羧基末端泛素加工蛋白酶，它可以在核内与 T-bet 相互作用。USP10 的过表达直接抑制 T-bet 的泛素化，增加 T-bet 的表达。我们进一步证实，槲皮素是一种报道的 T-bet 抑制剂，可以靶向 USP10。槲皮素处理以依赖蛋白酶体的方式下调 USP10 并促进 T-bet 降解。此外，我们发现哮喘患者 PBMC 中的 USP10 表达上调，这表明 USP10 可能维持高水平的 T-bet 和 IFN-γ 以对抗 Th2 占主导地位的炎症。
