Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
J Immunol. 2010 Aug 1;185(3):1593-605. doi: 10.4049/jimmunol.0903555. Epub 2010 Jul 7.
TNF-like weak inducer of apoptosis, TWEAK, is a typical member of the TNF ligand family. Thus, it is initially expressed as a type II transmembrane protein from which a soluble variant can be released by proteolytic processing. In this study, we show that membrane TWEAK is superior to soluble variant of TWEAK (sTWEAK) with respect to the activation of the classical NF-kappaB pathway, whereas both TWEAK variants are potent inducers of TNFR-associated factor-2 depletion, NF-kappaB-inducing kinase accumulation and p100 processing, hallmarks of activation of the noncanonical NF-kappaB pathway. Like other soluble TNF ligands with a poor capability to activate their corresponding receptor, sTWEAK acquires an activity resembling those of the transmembrane ligand by oligomerization or cell surface-immobilization. Blockade of the Fn14 receptor inhibited NF-kappaB signaling irrespective of the TWEAK form used for stimulation, indicating that the differential activities of the two TWEAK variants on classical and noncanonical NF-kappaB signaling is not related to the use of different receptors.
肿瘤坏死因子样弱凋亡诱导因子（TNF-like weak inducer of apoptosis，TWEAK）是肿瘤坏死因子配体家族的典型成员。因此，它最初作为一种 II 型跨膜蛋白表达，可通过蛋白水解处理释放可溶性变体。在本研究中，我们表明膜 TWEAK 在激活经典 NF-κB 途径方面优于 TWEAK 的可溶性变体（sTWEAK），而两种 TWEAK 变体均能有效诱导 TNFR 相关因子-2（TNFR-associated factor-2，TRAF2）耗竭、NF-κB 诱导激酶（NF-κB-inducing kinase，NIK）积累和 p100 加工，这是激活非经典 NF-κB 途径的标志。与其他缺乏激活相应受体能力的可溶性 TNF 配体一样，sTWEAK 通过寡聚化或细胞表面固定化获得类似于跨膜配体的活性。Fn14 受体阻断剂抑制 NF-κB 信号转导，与用于刺激的 TWEAK 形式无关，这表明两种 TWEAK 变体在经典和非经典 NF-κB 信号转导中的不同活性与使用不同受体无关。
