Institute of Biochemistry II, Goethe University Faculty of Medicine, 60590 Frankfurt am Main, Germany.
Institute of Biochemistry II, Goethe University Faculty of Medicine, 60590 Frankfurt am Main, Germany; Buchmann Institute for Molecular Life Sciences, Goethe University, 60438 Frankfurt am Main, Germany.
Mol Cell. 2014 May 8;54(3):349-61. doi: 10.1016/j.molcel.2014.03.016. Epub 2014 Apr 10.
Linear ubiquitin chains are implicated in the regulation of the NF-κB pathway, immunity, and inflammation. They are synthesized by the LUBAC complex containing the catalytic subunit HOIL-1-interacting protein (HOIP) and are disassembled by the linear ubiquitin-specific deubiquitinase OTULIN. Little is known about the regulation of these opposing activities. Here we demonstrate that HOIP and OTULIN interact and act as a bimolecular editing pair for linear ubiquitin signals in vivo. The HOIP PUB domain binds to the PUB interacting motif (PIM) of OTULIN and the chaperone VCP/p97. Structural studies revealed the basis of high-affinity interaction with the OTULIN PIM. The conserved Tyr56 of OTULIN makes critical contacts with the HOIP PUB domain, and its phosphorylation negatively regulates this interaction. Functionally, HOIP binding to OTULIN is required for the recruitment of OTULIN to the TNF receptor complex and to counteract HOIP-dependent activation of the NF-κB pathway.
线性泛素链参与 NF-κB 通路、免疫和炎症的调节。它们由包含催化亚基 HOIL-1 相互作用蛋白 (HOIP) 的 LUBAC 复合物合成，并被线性泛素特异性去泛素酶 OTULIN 分解。关于这些相反活性的调节知之甚少。在这里，我们证明 HOIP 和 OTULIN 相互作用，并在体内作为线性泛素信号的双分子编辑对发挥作用。HOIP 的 PUB 结构域与 OTULIN 的 PUB 相互作用基序 (PIM) 和伴侣蛋白 VCP/p97 结合。结构研究揭示了与 OTULIN PIM 高亲和力相互作用的基础。OTULIN 的保守 Tyr56 与 HOIP PUB 结构域形成关键接触，其磷酸化负调节这种相互作用。功能上，HOIP 与 OTULIN 的结合对于 OTULIN 招募到 TNF 受体复合物以及抵消 HOIP 依赖性 NF-κB 通路激活是必需的。
