B Cell Receptor-ERK1/2 Signal Cancels PAX5-Dependent Repression of BLIMP1 through PAX5 Phosphorylation: A Mechanism of Antigen-Triggering Plasma Cell Differentiation
B Cell Receptor-ERK1/2 Signal Cancels PAX5-Dependent Repression of BLIMP1 through PAX5 Phosphorylation: A Mechanism of Antigen-Triggering Plasma Cell Differentiation
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DOI：
10.4049/jimmunol.1103039
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发表时间：
2012-06
期刊：
影响因子：
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通讯作者：
T. Yasuda;F. Hayakawa;S. Kurahashi;K. Sugimoto;Y. Minami;A. Tomita;T. Naoe
中科院分区：
文献类型：
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作者：
T. Yasuda;F. Hayakawa;S. Kurahashi;K. Sugimoto;Y. Minami;A. Tomita;T. Naoe
浆细胞分化是由Ag刺激BCR启动的。在BCR刺激之前，B淋巴细胞诱导的成熟蛋白1（BLIMP 1）（浆细胞分化的主要调节物）被PAX 5抑制，PAX 5是维持B细胞身份的关键转录阻遏物。在BCR刺激后，观察到BLIMP 1的上调和随后的BLIMP 1对PAX 5的抑制，并认为这是浆细胞分化的触发因素;然而，解除BLIMP 1表达的触发因素尚未被揭示。在这项研究中，我们证明了PAX 5通过ERK 1/2磷酸化，ERK 1/2是BCR信号的主要成分。PAX 5磷酸化可解除PAX 5对BLIMP 1启动子的转录抑制作用。BCR刺激诱导B细胞中ERK 1/2活化、内源性PAX 5磷酸化和BLIMP 1 mRNA表达上调。这些现象被MEK 1抑制剂或PAX 5磷酸化缺陷突变所抑制。这些数据表明，PAX 5磷酸化的BCR信号是在浆细胞分化的初始事件。
Plasma cell differentiation is initiated by Ag stimulation of BCR. Until BCR stimulation, B lymphocyte-induced maturation protein 1 (BLIMP1), a master regulator of plasma cell differentiation, is suppressed by PAX5, which is a key transcriptional repressor for maintaining B cell identity. After BCR stimulation, upregulation of BLIMP1 and subsequent suppression of PAX5 by BLIMP1 are observed and thought to be the trigger of plasma cell differentiation; however, the trigger that derepresses BLIMP1 expression is yet to be revealed. In this study, we demonstrated PAX5 phosphorylation by ERK1/2, the main component of the BCR signal. Transcriptional repression on BLIMP1 promoter by PAX5 was canceled by PAX5 phosphorylation. BCR stimulation induced ERK1/2 activation, phosphorylation of endogenous PAX5, and upregulation of BLIMP1 mRNA expression in B cells. These phenomena were inhibited by MEK1 inhibitor or the phosphorylation-defective mutation of PAX5. These data imply that PAX5 phosphorylation by the BCR signal is the initial event in plasma cell differentiation.