Upon antigen stimulation, IgG⁺ B cells rapidly proliferate and differentiate into plasma cells, which has been attributed to the characteristics of membrane-bound IgG (mIgG), but the underlying molecular mechanisms remain elusive. We have found that a part of mouse mIgG1 is ubiquitinated through the two responsible lysine residues (K378 and K386) in its cytoplasmic tail and this ubiquitination is augmented upon antigen stimulation. The ubiquitination of mIgG1 involves its immunoglobulin tail tyrosine (ITT) motif, Syk/Src-family kinases and Cbl proteins. Analysis of a ubiquitination-defective mutant of mIgG1 revealed that ubiquitination of mIgG1 facilitates its ligand-induced endocytosis and intracellular trafficking from early endosome to late endosome, and also prohibits the recycling pathway, thus attenuating the surface expression level of mIgG1. Accordingly, ligation-induced activation of B-cell receptor (BCR) signalling molecules is attenuated by the mIgG1 ubiquitination, except MAP kinase p38 whose activation is up-regulated due to the ubiquitination-mediated prohibition of mIgG1 recycling. Adaptive transfer experiments demonstrated that ubiquitination of mIgG1 facilitates expansion of germinal centre B cells. These results indicate that mIgG1-mediated signalling and cell activation is regulated by ubiquitination of mIgG1, and such regulation may play a role in expansion of germinal centre B cells.

中文翻译：

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IgG1细胞质尾巴的泛素化调节B细胞信号传导和激活。

抗原刺激后，IgG ⁺B细胞迅速增殖并分化为浆细胞，这归因于膜结合IgG（mIgG）的特性，但潜在的分子机制仍然难以捉摸。我们已经发现，小鼠mIgG1的一部分通过其胞质尾中的两个负责的赖氨酸残基（K378和K386）被泛素化，并且这种泛素化作用在抗原刺激下得以增强。mIgG1的泛素化涉及其免疫球蛋白尾酪氨酸（ITT）基序，Syk / Src家族激酶和Cbl蛋白。对mIgG1的泛素化缺陷型突变体的分析表明，mIgG1的泛素化促进了其配体诱导的内吞作用以及从早期内体向晚期内体的细胞内运输，并且还禁止了再循环途径，从而减弱了mIgG1的表面表达水平。因此，连接诱导的B细胞受体（BCR）信号分子的激活被mIgG1泛素化减弱，除了MAP激酶p38的激活由于泛素介导的mIgG1再循环禁止而上调。适应性转移实验表明，mIgG1的泛素化促进生发中心B细胞的扩增。这些结果表明，mIgG1介导的信号传导和细胞活化受到mIgG1泛素化的调节，并且这种调节可能在生发中心B细胞的扩增中发挥作用。适应性转移实验表明，mIgG1的泛素化促进生发中心B细胞的扩增。这些结果表明，mIgG1介导的信号传导和细胞活化受到mIgG1泛素化的调节，并且这种调节可能在生发中心B细胞的扩增中发挥作用。适应性转移实验表明，mIgG1的泛素化促进生发中心B细胞的扩增。这些结果表明，mIgG1介导的信号传导和细胞活化受到mIgG1泛素化的调节，并且这种调节可能在生发中心B细胞的扩增中发挥作用。