肿瘤坏死因子受体相关因子2（TRAF2）在成熟B细胞中对核因子κB（NF-κB）激活的经典途径和非经典途径进行差异性调节。

TRAF2 differentially regulates the canonical and noncanonical pathways of NF-kappaB activation in mature B cells.

作者信息

Grech Adrian P, Amesbury Michelle, Chan Tyani, Gardam Sandra, Basten Antony, Brink Robert

机构信息

Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag No. 6, Newtown, NSW 2042, Australia.

出版信息

Immunity. 2004 Nov;21(5):629-42. doi: 10.1016/j.immuni.2004.09.011.

DOI:10.1016/j.immuni.2004.09.011

PMID:15539150

Abstract

To examine the role of the TNF-R superfamily signaling protein TRAF2 in mature B cell development and NF-kappaB activation, conditionally TRAF2-deficient mice were produced. B cells lacking TRAF2 expression in these mice possessed a selective survival advantage, accumulated in the lymph nodes and splenic marginal zone, were larger in size, and expressed increased levels of CD21/35. These TRAF2-deficient B cells could not proliferate or activate the canonical NF-kappaB pathway in response to CD40 ligation. By contrast, noncanonical NF-kappaB activation was constitutively hyperactive, with TRAF2-deficient B cells exhibiting close to maximal processing of NF-kappaB2 from p100 to p52 and high levels of constitutive p52 and RelB DNA binding activity. These findings establish TRAF2 as a multifunctional regulator of NF-kappaB activation that mediates activation of the canonical pathway but acts as a negative regulator of the noncanonical pathway. This dual functionality explains the contrasting roles of TRAF2 in B cell maturation and activation.

摘要

为了研究肿瘤坏死因子受体（TNF-R）超家族信号蛋白肿瘤坏死因子受体相关因子2（TRAF2）在成熟B细胞发育和核因子κB（NF-κB）激活中的作用，制备了条件性TRAF2缺陷小鼠。这些小鼠中缺乏TRAF2表达的B细胞具有选择性生存优势，在淋巴结和脾边缘区积聚，体积更大，并表达更高水平的CD21/35。这些TRAF2缺陷的B细胞在受到CD40连接时不能增殖或激活经典的NF-κB途径。相比之下，非经典NF-κB激活持续过度活跃，TRAF2缺陷的B细胞表现出从p100到p52的NF-κB2近乎最大程度的加工以及高水平的组成型p52和RelB DNA结合活性。这些发现确立了TRAF2作为NF-κB激活的多功能调节因子，它介导经典途径的激活，但作为非经典途径的负调节因子。这种双重功能解释了TRAF2在B细胞成熟和激活中的相反作用。