非典型 K27 连接的多泛素化 TIEG1 调节 Foxp3 表达和肿瘤生长。
Noncanonical K27-linked polyubiquitination of TIEG1 regulates Foxp3 expression and tumor growth.
机构信息
Karmanos Cancer Institute, Detroit, MI 48201, USA.
出版信息
J Immunol. 2011 May 15;186(10):5638-47. doi: 10.4049/jimmunol.1003801. Epub 2011 Apr 6.
Abstract
Earlier, we demonstrated the essential role of Kruppel-like transcription factor, TIEG1, in TGF-β-induced regulatory T cell (Treg) development. In this article, we demonstrate that IL-6, which promotes Th17 development, abrogated TIEG1 nuclear translocation and inhibited TGF-β-induced Treg development. Tyrosine kinase Tyk2-mediated phosphorylation of TIEG1 at Tyr179 promoted noncanonical K-27-linked polyubiquitination, which inhibited TIEG1 nuclear translocation. To test the role of TIEG1-regulated Treg/Th17 development in antitumor immunity, we analyzed TRAMP-C2 tumor growth in TIEG1(-/-) mice. The defective Treg development and elevated Th17 response resulted in enhanced immune reactivity in the tumor and inhibition of TRAMP-C2 tumor growth in TIEG1(-/-) mice. Thus, our results uncovered a novel regulatory mechanism that modulates Tregs and may regulate tumor progression.
摘要
早前，我们证实了 Kruppel 样转录因子 TIEG1 在 TGF-β 诱导调节性 T 细胞（Treg）发育中的重要作用。在本文中，我们证实了促进 Th17 细胞发育的白细胞介素 6（IL-6）可阻止 TIEG1 入核，并抑制 TGF-β 诱导的 Treg 细胞发育。TIEG1 的 Tyr179 酪氨酸激酶 Tyk2 介导的磷酸化促进非典型的 K-27 连接多聚泛素化，从而抑制 TIEG1 入核转位。为了检测 TIEG1 调节的 Treg/Th17 细胞发育在抗肿瘤免疫中的作用，我们分析了 TIEG1(-/-) 小鼠中 TRAMP-C2 肿瘤的生长情况。Treg 细胞发育缺陷和 Th17 反应增强导致肿瘤中的免疫反应增强，并抑制了 TIEG1(-/-) 小鼠中 TRAMP-C2 肿瘤的生长。因此，我们的研究结果揭示了一种新的调节机制，该机制可能调节 Treg 细胞，并可能调节肿瘤进展。
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