TRAF6 is a critical regulator of LMP1 functions in vivo
TRAF6 is a critical regulator of LMP1 functions in vivo
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DOI：
10.1093/intimm/dxt052
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发表时间：
2014-03-01
影响因子：
4.4
通讯作者：
Bishop, Gail A.
中科院分区：
文献类型：
--
作者：
Arcipowski, Kelly M.;Stunz, Laura L.;Bishop, Gail A.
TRAF6在体内介导LMP1的特异性作用。ebv编码的潜伏膜蛋白1 （LMP1）对ebv驱动的b细胞转化和大多数ebv相关的恶性肿瘤至关重要，也与自身免疫的加剧有关。LMP1在功能上模仿TNFR超家族成员CD40，但与CD40介导的信号和下游b细胞功能相比，LMP1诱导的信号和下游b细胞功能被放大和维持。CD40和LMP1都依赖于tnfr相关因子（TRAF）接头分子来介导信号传导，但使用它们的方式不同。LMP1依赖TRAFs 3和5来传递b细胞激活信号，而CD40主要使用TRAFs 2和6来实现这一目的。LMP1和CD40在B细胞中的功能都需要TRAF6， TRAF6通过不同的结合位点与这两种受体物理结合。在b细胞CD40信号传导中，TRAF6是体内CD40依赖性免疫功能的一个特定子集所必需的。由于CD40和LMP1使用其他TRAFs的方式不同，我们预测TRAF6对体内LMP1功能的特定子集至关重要，并且该子集将重叠但与CD40需要TRAF6的功能不同。本研究使用b细胞特异性traf6缺陷小鼠模型验证了这一预测。我们发现b细胞TRAF6对小鼠LMP1介导的抗体和自身抗体的产生以及生发中心的形成很重要，但对LMP1转基因表达导致的继发性淋巴器官的扩大不起作用。结果强调了LMP1与CD40对特定b细胞功能的TRAF6需求的差异。这些差异可能对正常调节的CD40与致病性lmp1介导的信号之间的差异做出了重要贡献。
TRAF6 mediates specific effects of LMP1 in vivo.EBV-encoded latent membrane protein 1 (LMP1) is critical for EBV-driven B-cell transformation and most EBV-associated malignancies and is also implicated in exacerbation of autoimmunity. LMP1 functionally mimics the TNFR superfamily member CD40, but LMP1-induced signals and downstream B-cell functions are amplified and sustained compared with those mediated by CD40. CD40 and LMP1 both depend upon TNFR-associated factor (TRAF) adaptor molecules to mediate signaling but use them differently. LMP1 is dependent upon TRAFs 3 and 5 to deliver B-cell activation signals, while CD40 predominantly uses TRAFs 2 and 6 for this purpose. Both LMP1 and CD40 functions in B cells require TRAF6, which physically associates with both receptors but via different binding sites. In B-cell CD40 signaling, TRAF6 is required for a particular subset of CD40-dependent immune functions in vivo. Inasmuch as CD40 and LMP1 use other TRAFs differentially, we predicted that TRAF6 is critical for a specific subset of LMP1 functions in vivo and that this subset will be overlapping but distinct from the TRAF6-requiring functions of CD40. This study tests this prediction using a B-cell-specific TRAF6-deficient mouse model. We found that B-cell TRAF6 is important for LMP1-mediated antibody and autoantibody production in mice, as well as germinal center formation, but not the secondary lymphoid organ enlargement that results from LMP1 transgenic expression. Results highlight differential TRAF6 requirements for specific B-cell functions by LMP1 versus CD40. These differences may make important contributions to the contrasts between normally regulated CD40 versus pathogenic LMP1-mediated signals.