Ras-ERK MAPK Cascade Regulates GATA3 Stability and Th2 Differentiation through Ubiquitin-Proteasome Pathway*
Ras-ERK MAPK Cascade Regulates GATA3 Stability and Th2 Differentiation through Ubiquitin-Proteasome Pathway*
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DOI：
10.1074/jbc.m502333200
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发表时间：
2005-08
影响因子：
4.8
通讯作者：
M. Yamashita;Ryo Shinnakasu;Hikari K. Asou;M. Kimura;A. Hasegawa;K. Hashimoto;Naoya Hatano;Masato Ogata;T. Nakayama
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文献类型：
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作者：
M. Yamashita;Ryo Shinnakasu;Hikari K. Asou;M. Kimura;A. Hasegawa;K. Hashimoto;Naoya Hatano;Masato Ogata;T. Nakayama
原生CD4 T细胞向Th2细胞的分化需要GATA3蛋白的表达。白细胞介素-4诱导STAT6激活和随后的GATA3转录。然而，关于T细胞受体介导的信号如何调节GATA3和Th2细胞分化，我们知之甚少。在这里，我们证明了T细胞受体介导的Ras-ERK MAPK级联激活通过抑制泛素-蛋白酶体途径稳定Th2细胞中的GATA3蛋白。Mdm2与GATA3相关并诱导GATA3泛素化，提示其作为GATA3泛素化的泛素蛋白异肽连接酶。因此，Ras-ERK MAPK级联通过转录后机制控制GATA3蛋白的稳定性，并促进GATA3介导的Th2细胞因子基因位点染色质重塑，导致Th2细胞成功分化。
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.