Noncanonical K27-linked polyubiquitination of TIEG1 regulates Foxp3 expression and tumor growth

• Published in: The Journal of immunology (1950) Vol. 186; no. 10; pp. 5638 - 5647
• Main Authors: Peng, Dong-Jun, Zeng, Minghui, Muromoto, Ryuta, Matsuda, Tadashi, Shimoda, Kazuya, Subramaniam, Malayannan, Spelsberg, Thomas C, Wei, Wei-Zen, Venuprasad, K
• Format: Journal Article
• Language: English
• Published: United States 15.05.2011
• Subjects: Active Transport, Cell Nucleus; Adoptive Transfer; Animals; Blotting, Western; Cell Nucleus - metabolism; Cell Proliferation; DNA-Binding Proteins - metabolism; Flow Cytometry; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Immunoprecipitation; Interleukin-6 - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Phosphorylation; Polymerase Chain Reaction; Receptors, Antigen, T-Cell - immunology; Signal Transduction; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Th17 Cells - metabolism; Transcription Factors - metabolism; Transforming Growth Factor beta - metabolism; TYK2 Kinase - metabolism; Ubiquitination
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1003801

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.