title: Noncanonical K27-linked polyubiquitination of TIEG1 regulates Foxp3 expression and tumor growth.
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.
authors.affiliation: Karmanos Cancer Institute, Detroit, MI 48201, USA.
authors.forename: Dong-Jun
authors.initials: DJ
authors.lastname: Peng
authors.forename: Minghui
authors.initials: M
authors.lastname: Zeng
authors.forename: Ryuta
authors.initials: R
authors.lastname: Muromoto
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsuda
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimoda
authors.forename: Malayannan
authors.initials: M
authors.lastname: Subramaniam
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Spelsberg
authors.forename: Wei-Zen
authors.initials: WZ
authors.lastname: Wei
authors.forename: K
authors.initials: K
authors.lastname: Venuprasad
mesh_terms: D021581:Active Transport, Cell Nucleus; D019264:Adoptive Transfer; D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D053634:TYK2 Kinase / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D054875:Ubiquitination; D051741:Kruppel-Like Transcription Factors; D051765:Early Growth Response Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D015850:Interleukin-6; D011948:Receptors, Antigen, T-Cell; D053634:TYK2 Kinase; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C498833:Foxp3 protein, mouse; C569958:KLF10 protein, mouse; D051741:Kruppel-Like Transcription Factors; D051765:Early Growth Response Transcription Factors