RACK1 competes with HSP90 for binding to HIF-1α and is required for O2-independent and HSP90 inhibitor-induced degradation of HIF-1α
RACK1 competes with HSP90 for binding to HIF-1α and is required for O2-independent and HSP90 inhibitor-induced degradation of HIF-1α
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DOI：
10.1016/j.molcel.2007.01.001
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发表时间：
2007-01-26
期刊：
影响因子：
16
通讯作者：
Semenza, Gregg L.
中科院分区：
文献类型：
--
作者：
Liu, Ye V.;Baek, Jin H.;Semenza, Gregg L.
低氧诱导因子1（HIF-1）响应于O2浓度的变化调节转录。HIF-1 α亚基的O-2依赖性降解由脯氨酰羟化酶（PHD）、von Hippel-Lindau（VHL）/Elongin-C/Elongin-B E3泛素连接酶复合物和蛋白酶体介导。抑制热休克蛋白90（HSP 90）导致HIF-1的O-2/PHDNHL非依赖性降解。我们已经确定了活化蛋白激酶C（RACK 1）的受体作为HIF-1 α相互作用的蛋白，促进PHD/VHL非依赖性蛋白酶体降解HIF-1 α。RACK 1与HSP 90在体外和人细胞中竞争结合HIF-1 α的PAS-A结构域。由HSP 90抑制剂17-烯丙基-氨基格尔德霉素诱导的HIF-1 α降解被RACK 1功能丧失所消除。RACK 1与延伸蛋白C结合并促进HIF-1 α的泛素化。RACK 1和VHL中的延伸蛋白C结合位点显示出显著的序列相似性。因此，RACK 1是O-2/PHD/VHL非依赖性机制的重要组成部分，该机制通过与HSP 90竞争和募集Elongin-C/B泛素连接酶复合物来调节HIF-1 α稳定性。
Hypoxia-inducible factor 1 (HIF-1) regulates transcription in response to changes in 02 concentration. O-2-dependent degradation of the HIF-1 a subunit is mediated by prolyl hydroxylase (PHD), the von Hippel-Lindau (VHL)/Elongin-C/Elongin-B E3 ubiquitin ligase complex, and the proteasome. Inhibition of heat-shock protein 90 (HSP90) leads to O-2/PHDNHL-independent degradation of HIF-1 . We have identified the receptor of activated protein kinase C (RACK1) as a HIF-1 alpha-interacting protein that promotes PHD/VHL-independent proteasomal degradation of HIF-1 alpha. RACK1 competes with HSP90 for binding to the PAS-A domain of HIF-1 alpha in vitro and in human cells. HIF-1 alpha degradation induced by the HSP90 inhibitor 17-allyl-aminogeldanamycin is abolished by RACK1 loss of function. RACK1 binds to Elongin-C and promotes ubiquitination of HIF-1 alpha. Elongin-C-binding sites in RACK1 and VHL show significant sequence similarity. Thus, RACK1 is an essential component of an O-2/PHD/VHL-independent mechanism for regulating HIF-loc stability through competition with HSP90 and recruitment of the Elongin-C/B ubiquitin ligase complex.