The COP9/signalosome increases the efficiency of von hippel-lindau protein ubiquitin ligase-mediated hypoxia-inducible factor-α ubiquitination
The COP9/signalosome increases the efficiency of von hippel-lindau protein ubiquitin ligase-mediated hypoxia-inducible factor-α ubiquitination
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DOI：
10.1074/jbc.m710599200
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发表时间：
2008-06-13
影响因子：
4.8
通讯作者：
Iwai, Kazuhiro
中科院分区：
文献类型：
--
作者：
Miyauchi, Yasuhiro;Kato, Michiko;Iwai, Kazuhiro
(von Hippel-Lindau 蛋白)-Elongin B/C-Cullin2-Rbx1 (VBC-Cul2) 泛素连接酶（Cullin-RING 泛素连接酶 (CRL) 的成员）对缺氧诱导因子 (HIF-α) 的 α 亚基进行氧依赖性泛素化，在控制氧代谢中发挥着核心作用。 Nedd8 与 cullin 的缀合增强了 CRL 的连接酶活性，并且 COP9/信号体 (CSN) 增强了几种 CRL 底物的降解，尽管它从 cullin 中去除了 Nedd8。在这里，我们证明，CSN 通过促进泛素化底物从复合物的 pVHL 亚基解离，提高了 VBC-Cul2 复合物识别和泛素化底物的效率。此外，CSN 通过促进细胞中 HIF-1 α 从 pVHL 解离来增强 HIF-1 α 降解。与底物缀合的多聚泛素链的长度似乎参与 CSN 介导的底物与 pVHL 的解离。与 CSN 介导的 CRL 激活的其他机制相比，泛素化底物从 pVHL 解离不需要 CSN 的去甲基化活性，这意味着 CSN 通过多种机制增强 CRL 底物的降解。
Oxygen-dependent ubiquitination of the alpha-subunit of hypoxia-inducible factor (HIF-alpha) by the (von Hippel-Lindau protein)-Elongin B/C-Cullin2-Rbx1 (VBC-Cul2) ubiquitin ligase, a member of the cullin-RING ubiquitin ligases (CRLs), plays a central role in controlling oxygen metabolism. Nedd8 conjugation of cullins enhances the ligase activity of CRLs, and the COP9/ signalosome (CSN) enhances the degradation of several CRL substrates, although it removes Nedd8 from cullins. Here we demonstrate that CSN increased the efficiency of the VBC-Cul2 complex for recognizing and ubiquitinating substrates by facilitating the dissociation of ubiquitinated substrates from the pVHL subunit of the complex. Moreover CSN enhanced HIF-1 alpha degradation by promoting the dissociation of HIF-1 alpha from pVHL in cells. The length of the polyubiquitin chain conjugated to the substrate appeared to be involved in CSN-mediated dissociation of the substrate from pVHL. In contrast to other mechanisms underlying CSN-mediated activation of CRLs, the dissociation of ubiquitinated substrates from pVHL did not require the deneddylation activity of CSN, implying that CSN enhances degradation of CRL substrates by multiple mechanisms.