Gfi1-mediated stabilization of GATA3 protein is required for Th2 cell differentiation.
The differentiation of naive CD4 T cells into Th2 cells requires the T cell receptor-mediated activation of the ERK MAPK cascade. Little is known, however, in regard to how the ERK MAPK cascade regulates Th2 cell differentiation. We herein identified Gfi1 (growth factor independent-1) as a downstream target of the ERK MAPK cascade for Th2 cell differentiation. In the absence of Gfi1, interleukin-5 production and the change of histone modification at the interleukin-5 gene locus were severely impaired. Furthermore, the interferon gamma gene showed a striking activation in the Gfi1(-/-) Th2 cells. An enhanced ubiquitin/proteasome-dependent degradation of GATA3 protein was observed in Gfi1(-/-) Th2 cells, and the overexpression of GATA3 eliminated the defect of Th2 cell function in Gfi1-deficient Th2 cells. These data suggest that the T cell receptor-mediated induction of Gfi1 controls Th2 cell differentiation through the regulation of GATA3 protein stability.
Shinnakasu
Ryo
R
Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba 260-8670, Japan.
Yamashita
Masakatsu
M
Kuwahara
Makoto
M
Hosokawa
Hiroyuki
H
Hasegawa
Akihiro
A
Motohashi
Shinichiro
S
Nakayama
Toshinori
T
D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D015848:Interleukin-5 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry
D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; C079873:Gfi1 protein, mouse; D015848:Interleukin-5; D014157:Transcription Factors; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex