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

J Immunol. 2011 May 15;186(10):5638-47. doi: 10.4049/jimmunol.1003801. Epub 2011 Apr 6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 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
  • TYK2 Kinase / metabolism
  • Th17 Cells / metabolism
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta / metabolism
  • Ubiquitination


  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-6
  • Receptors, Antigen, T-Cell
  • Tieg1 protein, mouse
  • Transcription Factors
  • Transforming Growth Factor beta
  • TYK2 Kinase