β-Arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2
β-Arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2
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DOI：
10.1073/pnas.0901083106
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发表时间：
2009-04-21
影响因子：
11.1
通讯作者：
Lefkowitz, Robert J.
中科院分区：
文献类型：
--
作者：
Shenoy, Sudha K.;Modi, Aalok S.;Lefkowitz, Robert J.
β - arrestins是介导7种跨膜受体（7TMRs）的脱敏、内化和一些信号功能的多功能适配器。由E3泛素连接酶Mdm2介导的激动剂刺激的β -arrestin2泛素化对于β(2)-肾上腺素能受体（β (2)AR）的快速内化至关重要。我们现在报告发现，去泛素化酶泛素特异性蛋白酶33 （USP33）结合β -arrestin2并导致β -arrestin2的去泛素化。USP33和Mdm2相互作用，分别有利于受体-抑制素复合物的稳定性或稳定性，从而调节受体信号体的寿命和亚细胞定位。像β (2)AR这样的受体，以前被证明与β -抑制素（“A类”）形成松散的复合物，促进有利于与去泛素酶结合的β -抑制素构象，而加压素V2R形成紧密的β -抑制素复合物（“B类”），促进独特的β -抑制素构象，有利于酶的解离。因此，usp33 - β -阻滞蛋白相互作用是7TMR运输和信号从活化受体传递到下游效应器的关键调控步骤。
beta-Arrestins are multifunctional adaptors that mediate the desensitization, internalization, and some signaling functions of seven-transmembrane receptors (7TMRs). Agonist-stimulated ubiquitination of beta-arrestin2 mediated by the E3 ubiquitin ligase Mdm2 is critical for rapid beta(2)-adrenergic receptor (beta(2)AR) internalization. We now report the discovery that the deubiquitinating enzyme ubiquitin-specific protease 33 (USP33) binds beta-arrestin2 and leads to the deubiquitination of beta-arrestins. USP33 and Mdm2 function reciprocally and favor respectively the stability or lability of the receptor beta-arrestin complex, thus regulating the longevity and subcellular localization of receptor signalosomes. Receptors such as the beta(2)AR, previously shown to form loose complexes with beta-arrestin ("class A") promote a beta-arrestin conformation conducive for binding to the deubiquitinase, whereas the vasopressin V2R, which forms tight beta-arrestin complexes ("class B"), promotes a distinct beta-arrestin conformation that favors dissociation of the enzyme. Thus, USP33-beta-arrestin interaction is a key regulatory step in 7TMR trafficking and signal transmission from the activated receptors to downstream effectors.