TY - JOUR
T1 - Noncanonical K27-linked polyubiquitination of TIEG1 regulates Foxp3 expression and tumor growth
AU - Peng, Dong Jun
AU - Zeng, Minghui
AU - Muromoto, Ryuta
AU - Matsuda, Tadashi
AU - Shimoda, Kazuya
AU - Subramaniam, Malayannan
AU - Spelsberg, Thomas C.
AU - Wei, Wei Zen
AU - Venuprasad, K.
PY - 2011/5/15
Y1 - 2011/5/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1003801
DO - 10.4049/jimmunol.1003801
M3 - Article
C2 - 21471442
AN - SCOPUS:79956194738
SN - 0022-1767
VL - 186
SP - 5638
EP - 5647
JO - Journal of Immunology
JF - Journal of Immunology
IS - 10
ER -