Ras-ERK MAPK cascade regulates GATA3 stability and Th2 differentiation through ubiquitin-proteasome pathway.
Differentiation of naive CD4 T cells into Th2 cells requires protein expression of GATA3. Interleukin-4 induces STAT6 activation and subsequent GATA3 transcription. Little is known, however, on how T cell receptor-mediated signaling regulates GATA3 and Th2 cell differentiation. Here we demonstrated that T cell receptor-mediated activation of the Ras-ERK MAPK cascade stabilizes GATA3 protein in developing Th2 cells through the inhibition of the ubiquitin-proteasome pathway. Mdm2 was associated with GATA3 and induced ubiquitination on GATA3, suggesting its role as a ubiquitin-protein isopeptide ligase for GATA3 ubiquitination. Thus, the Ras-ERK MAPK cascade controls GATA3 protein stability by a post-transcriptional mechanism and facilitates GATA3-mediated chromatin remodeling at Th2 cytokine gene loci leading to successful Th2 cell differentiation.
Yamashita
Masakatsu
M
Department of Immunology, Graduate School of Medicine, Chiba University, Japan.
Shinnakasu
Ryo
R
Asou
Hikari
H
Kimura
Motoko
M
Hasegawa
Akihiro
A
Hashimoto
Kahoko
K
Hatano
Naoya
N
Ogata
Masato
M
Nakayama
Toshinori
T
D000107:Acetylation; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D050990:GATA3 Transcription Factor; D006657:Histones / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2; D018418:Th2 Cells / Q000166:cytology*; D015534:Trans-Activators / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D016335:Zinc Fingers; D018631:ras Proteins / Q000502:physiology*
D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D006657:Histones; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D025801:Ubiquitin; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex; D018631:ras Proteins