Hatada Eunice N, Do Richard K G, Orlofsky Amos, Liou Hsiou-Chi, Prystowsky Michael, MacLennan Ian C M, Caamano Jorge, Chen-Kiang Selina
Department of Pathology, Cornell-Rockefeller University-Sloan-Kettering Institute Tri-Institutional MD-PhD Program, Weill Medical College of Cornell University, New York, NY, 10021, USA.
J Immunol. 2003 Jul 15;171(2):761-8. doi: 10.4049/jimmunol.171.2.761.
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.
B淋巴细胞刺激因子（BLyS）是一种对外周B细胞发育至关重要的肿瘤坏死因子家族蛋白，主要通过减弱B细胞凋亡发挥作用。在本研究中，我们发现BLyS在静止的成熟B细胞中通过经典和替代途径激活核因子κB（NF-κB），且动力学不同。它迅速且短暂地增强p50/p65 DNA结合活性，并诱导经典NF-κB途径特有的IκBα磷酸化，尽管通过持续的蛋白质合成和蛋白酶体介导的降解使IκBα维持在恒定水平。动力学延迟时，BLyS通过替代NF-κB途径促进p100加工成p52以及p52/RelB复合物的持续形成。p50对p100加工并非必需。然而，它对于介导体外静止成熟B细胞中最初的BLyS存活信号及伴随的Bcl-x(L)激活是必需的。尽管A1基因中的至少一个基因A1-a也是BLyS激活的靶点，但它对BLyS的存活功能并非必需。这些结果表明，BLyS至少部分地通过协调激活两条NF-κB途径和选择性下游抗凋亡基因，在代谢受限的静止B细胞中介导其存活信号。
