RHOBTB3 promotes proteasomal degradation of HIFα through facilitating hydroxylation and suppresses the Warburg effect.
RHOBTB3 promotes proteasomal degradation of HIFα through facilitating hydroxylation and suppresses the Warburg effect.
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RHOBTB3 通过促进羟基化促进 HIFα 的蛋白酶体降解并抑制 Warburg 效应。
DOI：
10.1038/cr.2015.90
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发表时间：
2015-09
期刊：
影响因子：
44.1
通讯作者：
Lin SC
中科院分区：
文献类型：
--
作者：
Zhang CS;Liu Q;Li M;Lin SY;Peng Y;Wu D;Li TY;Fu Q;Jia W;Wang X;Ma T;Zong Y;Cui J;Pu C;Lian G;Guo H;Ye Z;Lin SC
低氧诱导因子（Hypoxia-inducible factors，HIFs）是低氧适应性反应的主要调节因子，其α亚基在羟化后通过泛素化依赖的蛋白酶体途径迅速降解。HIF的异常积累或激活与许多类型的癌症密切相关。然而，HIFα的羟基化及其传递到泛素化机制的调节方式仍不清楚。我们发现Rho相关的BTB结构域蛋白3（RHOBTB 3）直接与羟化酶PHD 2相互作用，促进HIFα的羟基化。RHOBTB 3还直接与von Hippel-Lindau（VHL）蛋白（E3泛素连接酶复合物的一种组分）相互作用，促进HIFα的泛素化。值得注意的是，RHOBTB 3与LIMD 1二聚化，并构建RHOBTB 3/LIMD 1-PHD 2-VHL-HIFα复合物以实现HIFα的最大降解。缺氧减少了以RHOBTB 3为中心的复合物的形成，导致HIFα的积累。重要的是，RHOBTB 3的表达水平在人肾癌中大大降低，并且RHOBTB 3缺乏显著提高了瓦尔堡效应并加速异种移植物生长。因此，我们的工作表明，RHOBTB 3作为一个支架，组织一个多亚基复合物，促进羟基化，泛素化和降解的HIFα。
Hypoxia-inducible factors (HIFs) are master regulators of adaptive responses to low oxygen, and their α-subunits are rapidly degraded through the ubiquitination-dependent proteasomal pathway after hydroxylation. Aberrant accumulation or activation of HIFs is closely linked to many types of cancer. However, how hydroxylation of HIFα and its delivery to the ubiquitination machinery are regulated remains unclear. Here we show that Rho-related BTB domain-containing protein 3 (RHOBTB3) directly interacts with the hydroxylase PHD2 to promote HIFα hydroxylation. RHOBTB3 also directly interacts with the von Hippel-Lindau (VHL) protein, a component of the E3 ubiquitin ligase complex, facilitating ubiquitination of HIFα. Remarkably, RHOBTB3 dimerizes with LIMD1, and constructs a RHOBTB3/LIMD1-PHD2-VHL-HIFα complex to effect the maximal degradation of HIFα. Hypoxia reduces the RHOBTB3-centered complex formation, resulting in an accumulation of HIFα. Importantly, the expression level of RHOBTB3 is greatly reduced in human renal carcinomas, and RHOBTB3 deficiency significantly elevates the Warburg effect and accelerates xenograft growth. Our work thus reveals that RHOBTB3 serves as a scaffold to organize a multi-subunit complex that promotes the hydroxylation, ubiquitination and degradation of HIFα.