Regulation of receptor fate by ubiquitination of activated β2-adrenergic receptor and β-arrestin
Regulation of receptor fate by ubiquitination of activated β2-adrenergic receptor and β-arrestin
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DOI：
10.1126/science.1063866
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发表时间：
2001-11-09
期刊：
影响因子：
56.9
通讯作者：
Lefkowitz, RJ
中科院分区：
文献类型：
--
作者：
Shenoy, SK;McDonald, PH;Lefkowitz, RJ
虽然运输和降解的几种膜蛋白的调节泛素化催化E3泛素连接酶，已经有很少的证据连接泛素化与哺乳动物G蛋白（异源三聚体鸟嘌呤核苷酸结合蛋白）偶联受体（GPCR）功能的调节。内源性或转染的β（2）-肾上腺素能受体（β（2）AR）的激动剂刺激导致受体和受体调节蛋白β-抑制蛋白的快速泛素化。此外，蛋白酶体抑制剂减少了受体的内化和降解，从而暗示了泛素化机制在β 2 AR运输中的作用。受体泛素化需要β-抑制蛋白，其与E3泛素连接酶Mdm 2结合。通过在Mdm 2缺失细胞中表达或通过缺乏E3连接酶活性的Mdm 2的显性阴性形式消除β-抑制蛋白泛素化，抑制受体内化，对受体降解具有边际效应。然而，一个β（2）AR突变体tacking赖氨酸残基，这是不是泛素化，内化正常，但降解无效。这些发现描绘了β-抑制蛋白在介导β（2）AR的泛素化中的适配器作用，并表明受体和β-抑制蛋白的泛素化在这种原型GPCR的运输和降解中具有独特的和强制性的作用.
Although trafficking and degradation of several membrane proteins are regulated by ubiquitination catalyzed by E3 ubiquitin ligases, there has been little evidence connecting ubiquitination with regulation of mammalian G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) function. Agonist stimulation of endogenous or transfected beta (2)-adrenergic receptors (beta (2)ARs) led to rapid ubiquitination of both the receptors and the receptor regulatory protein, beta -arrestin. Moreover, proteasome inhibitors reduced receptor internalization and degradation, thus implicating a role for the ubiquitination machinery in the trafficking of the beta (2)AR. Receptor ubiquitination required beta -arrestin, which bound to the E3 ubiquitin ligase Mdm2. Abrogation of beta -arrestin ubiquitination, either by expression in Mdm2-null cells or by dominant-negative forms of Mdm2 lacking E3 ligase activity, inhibited receptor internalization with marginal effects on receptor degradation. However, a beta (2)AR mutant tacking lysine residues, which was not ubiquitinated, was internalized normally but was degraded ineffectively. These findings delineate an adapter role of beta -arrestin in mediating the ubiquitination of the beta (2)AR and indicate that ubiquitination of the receptor and of beta -arrestin have distinct and obligatory roles in the trafficking and degradation of this prototypic GPCR.