YOD1/TRAF6 association balances p62-dependent IL-1 signaling to NF-κB
YOD1/TRAF6 association balances p62-dependent IL-1 signaling to NF-κB
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DOI：
10.7554/elife.22416
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发表时间：
2017-02-28
期刊：
影响因子：
7.7
通讯作者：
Krappmann, Daniel
中科院分区：
文献类型：
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作者：
Schimmack, Gisela;schorpp, kenji;Krappmann, Daniel
泛素连接酶TRAF6是白细胞介素1(IL-1)刺激下Ikappa B激酶(IKK)/核因子-kappaB信号转导的关键调节因子。在这里，我们发现脱泛素化酶YOD1(OTUD2)是人类细胞中一种新的TRAF6的相互作用因子。YOD1与TRAF6的C-末端TRAF同源结构域结合，该结构域也是接头p62/Sequestosome-1的相互作用面，这是IL-1信号转导NF-kappa B所必需的。我们证明了YOD1与p62竞争TRAF6结合，并以非催化机制取消TRAF6与胞浆p62聚集体的结合。在未经刺激的细胞中，YOD1与TRAF6结合，但在IL-1β刺激下释放，从而促进TRAF6的自动泛素化以及NEMO/IKK伽马底物的泛素化。此外，IL-1触发的IKK/NF-kappa B信号转导和靶基因的诱导被YOD1过表达降低，并在YOD1缺失后增强。因此，我们的数据定义YOD1拮抗依赖于TRAF6/p62的IL-1对核因子-kappa B的信号转导。
The ubiquitin ligase TRAF6 is a key regulator of canonical I kappa B kinase (IKK)/NF-kappa B signaling in response to interleukin-1 (IL-1) stimulation. Here, we identified the deubiquitinating enzyme YOD1 (OTUD2) as a novel interactor of TRAF6 in human cells. YOD1 binds to the C-terminal TRAF homology domain of TRAF6 that also serves as the interaction surface for the adaptor p62/Sequestosome-1, which is required for IL-1 signaling to NF-kappa B. We show that YOD1 competes with p62 for TRAF6 association and abolishes the sequestration of TRAF6 to cytosolic p62 aggregates by a non-catalytic mechanism. YOD1 associates with TRAF6 in unstimulated cells but is released upon IL-1 beta stimulation, thereby facilitating TRAF6 auto-ubiquitination as well as NEMO/IKK gamma substrate ubiquitination. Further, IL-1 triggered IKK/NF-kappa B signaling and induction of target genes is decreased by YOD1 overexpression and augmented after YOD1 depletion. Hence, our data define that YOD1 antagonizes TRAF6/p62-dependent IL-1 signaling to NF-kappa B.