Parkin 通过介导 RIPK1 的位点特异性泛素化来调节 NF-κB。
Parkin regulates NF-κB by mediating site-specific ubiquitination of RIPK1.
机构信息
Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA, 02115, USA.
South China Sea Resource Exploitation and Protection Collaborative Innovation Center, Sun Yat-sen University, Guangzhou, 510275, P. R. China.
出版信息
Cell Death Dis. 2018 Jun 28;9(7):732. doi: 10.1038/s41419-018-0770-z.
Parkin (Park2), a RING-between-RING-type E3 ubiquitin ligase, has been implicated in regulating NF-κB. Mutations in Parkin are associated with Parkinson's disease. Here we investigated the interaction of Parkin with Receptor-interacting protein kinase 1 (RIPK1) kinase, a key mediator of multiple signaling pathways activated by TNFR1 including NF-κB pathway. We report that Parkin interacts with RIPK1 and mediates K63 ubiquitination of RIPK1 on K376 in TNFR1-signaling pathway. The expression of Parkin promotes the recruitment of transforming growth factor β (TGF-β)-activated kinase 1 (TAK1), nuclear factor-κB (NF-κB) essential molecule (NEMO), Sharpin and A20 in complex I associated with TNFR1 upon TNFα stimulation. Ubiquitination of RIPK1 by Parkin increases the activation of NF-κB and mitogen-activated protein kinases (MAPKs) by promoting the phosphorylation of inhibitor of kappa B kinase (IKK)α/β and IκBα and nuclear translocation of p65. Thus, we conclude that Parkin modulates the K63 ubiquitination status of RIPK1 to promote the activation of NF-κB and MAPKs.
Parkin（Park2），一种具有 RING-between-RING 结构的 E3 泛素连接酶，已被证实参与调节 NF-κB。Parkin 基因突变与帕金森病有关。在这里，我们研究了 Parkin 与受体相互作用蛋白激酶 1（RIPK1）激酶的相互作用，RIPK1 激酶是 TNFR1 激活的多种信号通路（包括 NF-κB 通路）的关键介质。我们报告 Parkin 与 RIPK1 相互作用，并介导 TNFR1 信号通路中 RIPK1 的 K376 上的 K63 泛素化。Parkin 的表达促进转化生长因子 β（TGF-β）激活激酶 1（TAK1）、核因子-κB（NF-κB）必需分子（NEMO）、Sharpin 和 A20 在 TNFα 刺激下与 TNFR1 相关复合物 I 的募集。Parkin 对 RIPK1 的泛素化增加了 NF-κB 和丝裂原激活蛋白激酶（MAPKs）的激活，促进了 IκB 激酶（IKK）α/β 和 IκBα 的磷酸化以及 p65 的核转位。因此，我们得出结论，Parkin 通过调节 RIPK1 的 K63 泛素化状态来促进 NF-κB 和 MAPKs 的激活。
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