标题：β-Arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：16
页码：6650-6655
DOI：10.1073/pnas.0901083106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：{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}2AR) 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}2AR, 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.
