TWEAK Inhibits TRAF2-Mediated CD40 Signaling by Destabilization of CD40 Signaling Complexes
TWEAK Inhibits TRAF2-Mediated CD40 Signaling by Destabilization of CD40 Signaling Complexes
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DOI：
10.4049/jimmunol.1202899
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发表时间：
2013-09-01
影响因子：
4.4
通讯作者：
Wajant, Harald
中科院分区：
文献类型：
--
作者：
Salzmann, Steffen;Lang, Isabell;Wajant, Harald
我们最近发现，肿瘤坏死因子样弱诱导因子(TWEEP)和成纤维细胞生长因子诱导因子-14(Fn14)由于其强大的减少可自由获得的TNFR相关因子(TRAF)2和细胞凋亡抑制因子(CIAPs)的能力而拮抗这些分子在TNFR1信号中的功能，从而导致细胞凋亡的增敏和经典的核因子-kappaB信号的抑制。在这项研究中，我们证明了TWEW对细胞的启动也干扰了CD40激活经典的核因子-kappaB途径。同样，CD40配体(CD40L)对TWEY诱导的细胞内MAPKs的激活也有很强的抑制作用。流式细胞仪分析和CD40L结合实验显示，TWEEP诱导的细胞CD40表达无明显变化，CD40L-CD40相互作用正常。然而，CD40L免疫沉淀物显示CD40和CD40相关蛋白的数量严重减少，表明CD40L-CD40信号复合体的形成受到损害或稳定性降低。先前所描述的TWEEP对TNFR1信号的抑制作用可以追溯到与TNFR1相关的TRAF2-cIAP1/2泛素酶复合体的活性降低，并且不影响可免疫沉淀的TNFR1受体复合体的稳定性。因此，TWEEP对CD40信号的抑制作用必须至少部分地基于其他机制。与此相一致，CD40相关的TRAF2相互作用受体TNFR2的信号也被减弱，但在TWEY诱导的细胞中仍可免疫沉淀。总之，我们发现通过可溶性TWEY激活Fn14会损害CD40L-CD40信号复合体的形成并抑制CD40信号，从而确定Fn14-TWEY系统是一种潜在的CD40相关细胞功能的新调节因子。
We found recently that TNF-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible-14 (Fn14) by virtue of their strong capability to reduce the freely available cytoplasmic pool of TNFR-associated factor (TRAF) 2 and cellular inhibitors of apoptosis (cIAPs) antagonize the functions of these molecules in TNFR1 signaling, resulting in sensitization for apoptosis and inhibition of classical NF-kappa B signaling. In this study, we demonstrate that priming of cells with TWEAK also interferes with activation of the classical NF-kappa B pathway by CD40. Likewise, there was strong inhibition of CD40 ligand (CD40L)-induced activation of MAPKs in TWEAK-primed cells. FACS analysis and CD40L binding studies revealed unchanged CD40 expression and normal CD40L-CD40 interaction in TWEAK-primed cells. CD40L immunoprecipitates, however, showed severely reduced amounts of CD40 and CD40-associated proteins, indicating impaired formation or reduced stability of CD40L-CD40 signaling complexes. The previously described inhibitory effect of TWEAK on TNFR1 signaling has been traced back to reduced activity of the TNFR1-associated TRAF2-cIAP1/2 ubiquitinase complex and did not affect the stability of the immunoprecipitable TNFR1 receptor complex. Thus, the inhibitory effect of TWEAK on CD40 signaling must be based at least partly on other mechanisms. In line with this, signaling by the CD40-related TRAF2-interacting receptor TNFR2 was also attenuated but still immunoprecipitable in TWEAK-primed cells. Collectively, we show that Fn14 activation by soluble TWEAK impairs CD40L-CD40 signaling complex formation and inhibits CD40 signaling and thus identify the Fn14-TWEAK system as a potential novel regulator of CD40-related cellular functions.