Notch-regulated periphery B cell differentiation involves suppression of E protein function.
Notch-regulated periphery B cell differentiation involves suppression of E protein function.
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DOI：
10.4049/jimmunol.1202134
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发表时间：
2013-07-15
期刊：
影响因子：
--
通讯作者：
Sun XH
中科院分区：
文献类型：
--
作者：
Zhang P;Zhao Y;Sun XH
Notch信号通路在外周B细胞成熟过程中以牺牲滤泡（FO）B细胞为代价促进边缘区（MZ）B细胞的产生发挥重要作用，但其潜在的分子机制尚不清楚。我们假设 Notch 通过下调 E 蛋白活性来促进 MZ B 细胞的产生。在这里，我们证明了 MZ B 细胞中 Id2 和含有锚蛋白重复 SOCS 盒的蛋白 2 (Asb2) 的表达通过 Notch 信号传导而升高。 Id2 抑制 E 蛋白的 DNA 结合活性，而 Asb2 促进 E 蛋白泛素化。接下来，我们检查了表达组成型活性 Notch1 和/或两种 E 蛋白功能获得突变体的小鼠中脾 B 细胞的表型，这些突变体抵消了 Id2 介导的抑制或 Notch 诱导的降解。我们发现E蛋白的上调促进了FO B细胞的形成，同时抑制了MZ B细胞的成熟。相反，过量的Notch1会刺激MZ B细胞的分化并抑制FO B细胞的产生。更有趣的是，Notch1 的影响因 E 蛋白功能的增强而逆转。此外，FO B 细胞中高水平的 Bcl-6 表达被 Notch 信号减弱，并被 E 蛋白恢复。此外，E蛋白促进过渡B细胞的分化，Notch阻碍其分化。综上所述，Notch 似乎至少部分通过对抗 E 蛋白功能来调节外周 B 细胞分化。
Notch signaling pathway plays important roles in promoting the generation of marginal zone (MZ) B cells at the expense of follicular (FO) B cells during periphery B cell maturation, but the underlying molecular mechanisms are not well understood. We hypothesize that Notch favors the generation of MZ B cells by down-regulating E protein activity. Here, we demonstrated that expression of Id2 and ankyrin-repeat SOCS box-containing protein 2 (Asb2) was elevated in MZ B cells and by Notch signaling. Id2 inhibits the DNA binding activity of E proteins whereas Asb2 facilitates E protein ubiquitination. Next, we examined the phenotypes of splenic B cells in mice expressing constitutively active Notch1 and/or two gain-of-function mutants of E proteins that counteract Id2-mediated inhibition or Notch-induced degradation. We found that up-regulation of E proteins promoted the formation of FO B cells while it suppressed the maturation of MZ B cells. In contrast, excessive amounts of Notch1 stimulated the differentiation of MZ B cells and inhibited the production of FO B cells. More interestingly, the effects of Notch1 were reversed by gain of E protein function. Furthermore, high levels of Bcl-6 expression in FO B cells was shown to be diminished by Notch signaling and restored by E proteins. In addition, E proteins facilitated and Notch hindered the differentiation of transitional B cells. Taken together, it appears that Notch regulates peripheral B cell differentiation, at least in part, through opposing E protein function.
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