Arrestin domain-containing protein 3 recruits the NEDD4 E3 ligase to mediate ubiquitination of the β2-adrenergic receptor
Arrestin domain-containing protein 3 recruits the NEDD4 E3 ligase to mediate ubiquitination of the β2-adrenergic receptor
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DOI：
10.1038/embor.2010.80
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发表时间：
2010-08-01
期刊：
影响因子：
7.7
通讯作者：
Lu, Quan
中科院分区：
文献类型：
--
作者：
Nabhan, Joseph F.;Pan, Hui;Lu, Quan
长时间刺激β 2-肾上腺素能受体（β 2AR）导致受体泛素化和下调。利用全基因组RNA干扰筛选，我们鉴定出含有抑制蛋白结构域3 （ARRDC3）是β 2AR调控所需的基因。ARRDC3蛋白通过两个保守的PPXY基序与泛素连接酶神经前体发育下调蛋白4 （NEDD4）相互作用，并将NEDD4招募到活化的受体。ARRDC3蛋白也与活化的β 2AR相互作用和共定位。敲低ARRDC3表达可消除NEDD4与β 2AR之间的关联。此外，通过小干扰RNA （siRNA）介导的敲低或不与NEDD4相互作用的突变体的过表达，ARRDC3的功能失活会阻断受体的泛素化和降解。我们的研究结果表明ARRDC3是β 2AR泛素化的重要适配器。
Prolonged stimulation of the beta 2-adrenergic receptor (beta 2AR) leads to receptor ubiquitination and downregulation. Using a genome-wide RNA interference screen, we identified arrestin domain-containing 3 (ARRDC3) as a gene required for beta 2AR regulation. The ARRDC3 protein interacts with ubiquitin ligase neural precursor development downregulated protein 4 (NEDD4) through two conserved PPXY motifs and recruits NEDD4 to the activated receptor. The ARRDC3 protein also interacts and co-localizes with activated beta 2AR. Knockdown of ARRDC3 expression abolishes the association between NEDD4 and beta 2AR. Furthermore, functional inactivation of ARRDC3, either through small interfering RNA (siRNA)-mediated knockdown or overexpression of a mutant that does not interact with NEDD4, blocks receptor ubiquitination and degradation. Our results establish ARRDC3 as an essential adaptor for beta 2AR ubiquitination.