Binding of OTULIN to the PUB Domain of HOIP Controls NF-κB Signaling
Binding of OTULIN to the PUB Domain of HOIP Controls NF-κB Signaling
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DOI：
10.1016/j.molcel.2014.03.016
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发表时间：
2014-05-08
期刊：
影响因子：
16
通讯作者：
Dikic, Ivan
中科院分区：
文献类型：
--
作者：
Schaeffer, Veronique;Akutsu, Masato;Dikic, Ivan
线性泛素链参与了核因子-kappaB途径、免疫和炎症的调节。它们是由含有催化亚单位HOIL-1相互作用蛋白(HOIP)的LUBAC复合体合成的，并被线性泛素特异性脱泛素酶OTULIN分解。人们对这些对立活动的监管知之甚少。在这里，我们证明了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。HOIP pub结构域与OTULIN的pub相互作用基序(PIM)和伴侣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保守的Tyr56与HOIP pub结构域发生关键接触，其磷酸化负向调节这种相互作用。在功能上，需要HOIP与OTULIN结合，才能将OTULIN重新招募到肿瘤坏死因子受体复合体，并抵消依赖HOIP的NF-kappa B途径的激活。
Linear ubiquitin chains are implicated in the regulation of the NF-kappa B 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-kappa B pathway.