Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Shenoy, SK; Modi, AS; Shukla, AK; Xiao, K; Berthouze, M; Ahn, S; Wilkinson, KD; Miller, WE; Lefkowitz, RJ
Published Date
- April 21, 2009
Published In
Volume / Issue
- 106 / 16
Start / End Page
- 6650 - 6655
PubMed ID
- 19363159
Pubmed Central ID
- PMC2667797
Electronic International Standard Serial Number (EISSN)
- 1091-6490
Digital Object Identifier (DOI)
- 10.1073/pnas.0901083106
Language
- eng
Conference Location
- United States