Pan Fan, Barbi Joseph
Immunology and Hematopoiesis Division, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA,
J Mol Med (Berl). 2014 Jun;92(6):555-69. doi: 10.1007/s00109-014-1156-z. Epub 2014 Apr 29.
Posttranslational modification by ubiquitin tagging is crucial for regulating the stability, activity and cellular localization of many target proteins involved in processes including DNA repair, cell cycle progression, protein quality control, and signal transduction. It has long been appreciated that ubiquitin-mediated events are important for certain signaling pathways leading to leukocyte activation and the stimulation of effector function. Now it is clear that the activities of molecules and pathways central to immune regulation are also modified and controlled by ubiquitin tagging. Among the mechanisms of immune control, regulatory T cells (or Tregs) are themselves particularly sensitive to such regulation. E3 ligases and deubiquitinases both influence Tregs through their effects on the signaling pathways pertinent to these cells or through the direct, posttranslational regulation of Foxp3. In this review, we will summarize and discuss several examples of ubiquitin-mediated control over multiple aspects of Treg biology including the generation, function and phenotypic fidelity of these cells. Fully explored and exploited, these potential opportunities for Treg modulation may lead to novel immunotherapies for both positive and negative fine-tuning of immune restraint.
通过泛素标记进行的翻译后修饰对于调节许多参与DNA修复、细胞周期进程、蛋白质质量控制和信号转导等过程的靶蛋白的稳定性、活性和细胞定位至关重要。长期以来，人们一直认识到泛素介导的事件对于某些导致白细胞活化和效应器功能刺激的信号通路很重要。现在很清楚，免疫调节核心分子和通路的活性也受到泛素标记的修饰和控制。在免疫控制机制中，调节性T细胞（或Tregs）本身对这种调节特别敏感。E3连接酶和去泛素化酶都通过影响与这些细胞相关的信号通路或通过对Foxp3的直接翻译后调节来影响Tregs。在这篇综述中，我们将总结并讨论泛素介导的对Treg生物学多个方面的控制的几个例子，包括这些细胞的产生、功能和表型保真度。充分探索和利用这些调节Treg的潜在机会，可能会带来用于免疫抑制正性和负性微调的新型免疫疗法。
