SPATA2 links CYLD to the TNF-α receptor signaling complex and modulates the receptor signaling outcomes
SPATA2 links CYLD to the TNF-α receptor signaling complex and modulates the receptor signaling outcomes
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DOI：
10.15252/embj.201694300
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发表时间：
2016-09-01
期刊：
影响因子：
11.4
通讯作者：
Choudhary, Chunaram
中科院分区：
文献类型：
--
作者：
Wagner, Sebastian A.;Satpathy, Shankha;Choudhary, Chunaram
TNF-α 是先天免疫和促炎反应的关键调节剂。然而，TNF-α受体相关信号复合物（TNF-RSC）的组成和下游信号网络的结构尚不完全清楚。我们采用定量质谱法来证明 TNF-α 刺激会诱导广泛的蛋白质磷酸化，并且磷酸化的范围会暂时扩大。 TNF-α 刺激还会诱导 TNF-RSC 成分快速泛素化。 TNF-RSC 成分的时间分析确定 SPATA2 是 TNF-RSC 的新成分。 SPATA2 N 端的预测 PUB 结构域与 CYLD 的 USP 结构域相互作用，而 SPATA2 C 端与 HOIP 相互作用。 SPATA2 是 CYLD 招募至 TNF-RSC 所必需的。 SPATA2 的下调增强了 NF-κ B 的转录激活并抑制 TNF-α 诱导的坏死性凋亡，表明 SPATA2 在调节 TNF-α 信号转导结果中具有重要功能。综上所述，我们的研究绘制了 TNF-α 信号传导的详细图谱，将 SPATA2 鉴定为 TNF-β 信号传导的新成分，并为进一步的功能研究提供了丰富的资源。
TNF-alpha is a key regulator of innate immune and proinflammatory responses. However, the composition of the TNF-alpha receptor-associated signaling complexes (TNF-RSC) and the architecture of the downstream signaling networks are incompletely understood. We employed quantitative mass spectrometry to demonstrate that TNF-alpha stimulation induces widespread protein phosphorylation and that the scope of phosphorylation expands in a temporal manner. TNF-alpha stimulation also induces rapid ubiquitylation of components of the TNF-RSC. Temporal analysis of the TNF-RSC composition identified SPATA2 as a novel component of the TNF-RSC. The predicted PUB domain in the N-terminus of SPATA2 interacts with the USP domain of CYLD, whereas the C-terminus of SPATA2 interacts with HOIP. SPATA2 is required for recruitment of CYLD to the TNF-RSC. Downregulation of SPATA2 augments transcriptional activation of NF-kappa B and inhibits TNF-alpha-induced necroptosis, pointing to an important function of SPATA2 in modulating the outcomes of TNF-alpha signaling. Taken together, our study draws a detailed map of TNF-alpha signaling, identifies SPATA2 as a novel component of TNF-beta signaling, and provides a rich resource for further functional investigations.