Schimmack Gisela, Schorpp Kenji, Kutzner Kerstin, Gehring Torben, Brenke Jara Kerstin, Hadian Kamyar, Krappmann Daniel
Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
Elife. 2017 Feb 28;6:e22416. doi: 10.7554/eLife.22416.
The ubiquitin ligase TRAF6 is a key regulator of canonical IκB kinase (IKK)/NF-κB 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-κB. 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-1β stimulation, thereby facilitating TRAF6 auto-ubiquitination as well as NEMO/IKKγ substrate ubiquitination. Further, IL-1 triggered IKK/NF-κB 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-κB.
泛素连接酶TRAF6是白细胞介素-1（IL-1）刺激下经典IκB激酶（IKK）/核因子κB（NF-κB）信号通路的关键调节因子。在此，我们鉴定去泛素化酶YOD1（OTUD2）为人类细胞中TRAF6的新型相互作用蛋白。YOD1与TRAF6的C端TRAF同源结构域结合，该结构域也是衔接蛋白p62/聚集体蛋白1的相互作用表面，而p62/聚集体蛋白1是IL-1信号传导至NF-κB所必需的。我们发现YOD1与p62竞争结合TRAF6，并通过非催化机制消除TRAF6与胞质p62聚集体的隔离。YOD1在未受刺激的细胞中与TRAF6结合，但在IL-1β刺激时释放，从而促进TRAF6自身泛素化以及NEMO/IKKγ底物泛素化。此外，YOD1过表达会降低IL-1触发的IKK/NF-κB信号传导和靶基因诱导，而YOD1缺失后则增强。因此，我们的数据表明YOD1拮抗TRAF6/p62依赖的IL-1向NF-κB的信号传导。
