NIK overexpression amplifies, whereas ablation of its TRAF3-binding domain replaces BAFF:BAFF-R-mediated survival signals in B cells
NIK overexpression amplifies, whereas ablation of its TRAF3-binding domain replaces BAFF:BAFF-R-mediated survival signals in B cells
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DOI：
10.1073/pnas.0805186105
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发表时间：
2008-08-05
影响因子：
11.1
通讯作者：
Schmidt-Supprian, Marc
中科院分区：
文献类型：
--
作者：
Sasaki, Yoshiteru;Calado, Dinis P.;Schmidt-Supprian, Marc
替代性NF-κ B途径的BAFF-R依赖性活化在成熟B细胞存活中起重要作用。导致NIK过表达和TRAF 3基因缺失的突变与人类多发性骨髓瘤有关。我们发现小鼠B淋巴细胞中NIK的过表达以BAFF-R依赖的方式放大了NF-κ B B的活化和外周B细胞的数量，而NIK与TRAF 3介导的对照解偶联导致最大的p100加工和BAFF-R非依赖性B细胞的显著增生。NIK通过以剂量依赖性方式增加其负调节因子TRAF 3的蛋白水平来控制备选NF-κ B信号传导。这种机制使NIK蛋白水平保持低于检测，即使当它们引起B细胞增生时，使得NIK对B细胞病理的贡献可以容易地被忽略。
BAFF-R-dependent activation of the alternative NF-kappa B pathway plays an essential role in mature B cell survival. Mutations leading to overexpression of NIK and deletion of the TRAF3 gene are implicated in human multiple myeloma. We show that overexpression of NIK in mouse B lymphocytes amplifies alternative NF-kappa B activation and peripheral B cell numbers in a BAFF-R-dependent manner, whereas uncoupling NIK from TRAF3-mediated control causes maximal p100 processing and dramatic hyperplasia of BAFF-R-independent B cells. NIK controls alternative NF-kappa B signaling by increasing the protein levels of its negative regulator TRAF3 in a dose-dependent fashion. This mechanism keeps NIK protein levels below detection even when they cause B cell hyperplasia, so that contributions of NIK to B cell pathologies can easily be overlooked.