A pathway switch directs BAFF signaling to distinct NFκB transcription factors in maturing and proliferating B cells.
A pathway switch directs BAFF signaling to distinct NFκB transcription factors in maturing and proliferating B cells.
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DOI：
10.1016/j.celrep.2014.11.024
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发表时间：
2014-12-24
期刊：
影响因子：
8.8
通讯作者：
Hoffmann A
中科院分区：
文献类型：
--
作者：
Almaden JV;Tsui R;Liu YC;Birnbaum H;Shokhirev MN;Ngo KA;Davis-Turak JC;Otero D;Basak S;Rickert RC;Hoffmann A
BAFF是非经典NFκB通路的激活剂，在B细胞成熟过程中提供关键的存活信号，并有助于B细胞增殖。我们发现，NFκB家族成员RelB是B细胞成熟所必需的，但cRel是增殖所必需的。结合分子网络建模和实验显示Nfkb 2 p100是一个通路开关;在成熟B细胞中，在中等p100合成速率下，BAFF充分利用p100生成RelB：p52二聚体，而在高合成速率下，p100组装成多聚体IκBsome复合物，BAFF中和该复合物以增强cRel活性和B细胞扩增。事实上，p100表达的调节或IκBsome组装的破坏规避了完整B细胞扩增的BAFF要求。我们的研究强调了p100在B细胞生物学过程中决定不同NFκB网络状态的重要性，这导致BAFF具有上下文依赖性功能后果。
BAFF, an activator of the noncanonical NFκB pathway, provides critical survival signals during B cell maturation and contributes to B cell proliferation. We found that the NFκB family member RelB is required ex vivo for B cell maturation, but cRel is required for proliferation. Combined molecular network modeling and experimentation revealed Nfkb2 p100 as a pathway switch; at moderate p100 synthesis rates in maturing B cells, BAFF fully utilizes p100 to generate the RelB:p52 dimer, whereas at high synthesis rates, p100 assembles into multimeric IκBsome complexes, which BAFF neutralizes in order to potentiate cRel activity and B cell expansion. Indeed, moderation of p100 expression or disruption of IκBsome assembly circumvented the BAFF requirement for full B cell expansion. Our studies emphasize the importance of p100 in determining distinct NFκB network states during B cell biology, which causes BAFF to have context-dependent functional consequences.