NF-κB1 p50 is required for BLyS attenuation of apoptosis but dispensable for processing of NF-κB2 p100 to p52 in quiescent mature B cells
NF-κB1 p50 is required for BLyS attenuation of apoptosis but dispensable for processing of NF-κB2 p100 to p52 in quiescent mature B cells
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DOI：
10.4049/jimmunol.171.2.761
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发表时间：
2003-07-15
影响因子：
4.4
通讯作者：
Chen-Kiang, S
中科院分区：
文献类型：
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作者：
Hatada, EN;Do, RKG;Chen-Kiang, S
B 淋巴细胞刺激因子 (BLyS) 是一种对于外周 B 细胞发育至关重要的 TNF 家族蛋白，主要通过减弱 B 细胞凋亡发挥作用。在这项研究中，我们证明 BLyS 通过经典途径和替代途径激活 NF-kappaB，在静止的成熟 B 细胞中具有不同的动力学。它快速、短暂地增强 p50/p65 DNA 结合活性，并诱导经典 NF-kappaB 途径特有的 IkappaBalpha 磷酸化，同时通过持续的蛋白质合成和蛋白酶体介导的破坏将 IkappaBalpha 维持在恒定水平。通过延迟动力学，BLyS 促进 p100 加工成 p52，并通过替代 NF-kappaB 途径持续形成 p52/RelB 复合物。 p50对于p100处理来说是可有可无的。然而，它需要介导初始 BLyS 存活信号以及离体静息成熟 B 细胞中 Bcl-x(L) 的伴随激活。尽管 A1 基因 A1-a 也是 BLyS 激活的靶标，但它对于 BLyS 生存功能来说是可有可无的。这些结果表明，BLyS 至少部分通过协调激活 NF-kappaB 通路和选择性下游抗凋亡基因，在代谢受限的静止 B 细胞中介导其生存信号。
B lymphocyte stimulator (BLyS), a TNF family protein essential for peripheral B cell development, functions primarily through attenuation of B cell apoptosis. In this study, we show that BLyS activates NF-kappaB through both classical and alternative pathways with distinct kinetics in quiescent mature B cells. It rapidly and transiently enhances the p50/p65 DNA binding activity and induces phosphorylation of IkappaBalpha characteristic of the classical NF-kappaB pathway, albeit maintaining IkappaBalpha at a constant level through ongoing protein synthesis and proteasome-mediated destruction. With delayed kinetics, BLyS promotes the processing of p100 to p52 and sustained formation of p52/RelB complexes via the alternative NF-kappaB pathway. p50 is dispensable for p100 processing. However, it is required to mediate the initial BLyS survival signals and concomitant activation of Bcl-x(L) in quiescent mature B cells ex vivo. Although also a target of BLyS activation, at least one of the A1 genes, A1-a, is dispensable for the BLyS survival function. These results suggest that BLyS mediates its survival signals in metabolically restricted quiescent B cells, at least in part, through coordinated activation of both NF-kappaB pathways and selective downstream antiapoptotic genes.