Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
J Exp Med. 2010 Nov 22;207(12):2569-79. doi: 10.1084/jem.20100857. Epub 2010 Nov 1.
The cytokine B cell activating factor (BAFF) and its receptor, BAFF receptor (BAFF-R), modulate signaling cascades critical for B cell development and survival. We identified a novel mutation in TNFRSF13C, the gene encoding human BAFF-R, that is present in both tumor and germline tissue from a subset of patients with non-Hodgkin lymphoma. This mutation encodes a His159Tyr substitution in the cytoplasmic tail of BAFF-R adjacent to the TRAF3 binding motif. Signaling through this mutant BAFF-R results in increased NF-κB1 and NF-κB2 activity and increased immunoglobulin production compared with the wild-type (WT) BAFF-R. This correlates with increased TRAF2, TRAF3, and TRAF6 recruitment to His159Tyr BAFF-R. In addition, we document a requirement for TRAF6 in WT BAFF-R signaling. Together, these data identify a novel lymphoma-associated mutation in human BAFF-R that results in NF-κB activation and reveals TRAF6 as a necessary component of normal BAFF-R signaling.
细胞因子 B 细胞激活因子 (BAFF) 及其受体 BAFF 受体 (BAFF-R) 调节着对 B 细胞发育和存活至关重要的信号级联反应。我们在非霍奇金淋巴瘤患者的一部分肿瘤和生殖组织中发现了 TNFRSF13C（编码人类 BAFF-R 的基因）中的一个新突变。该突变在 BAFF-R 的细胞质尾部编码一个临近 TRAF3 结合基序的 His159Tyr 取代。与野生型 (WT) BAFF-R 相比，这种突变的 BAFF-R 信号转导导致 NF-κB1 和 NF-κB2 活性增加，免疫球蛋白产生增加。这与 TRAF2、TRAF3 和 TRAF6 募集到 His159Tyr BAFF-R 增加相关。此外，我们还证明了 TRAF6 在 WT BAFF-R 信号转导中的必要性。综上所述，这些数据确定了人类 BAFF-R 中一种新的淋巴瘤相关突变，导致 NF-κB 激活，并揭示了 TRAF6 是正常 BAFF-R 信号转导的必要组成部分。
