Journal
EMBO REPORTS
Volume 11, Issue 8, Pages 605-611Publisher
WILEY
DOI: 10.1038/embor.2010.80
Keywords
ARRDC3; arrestin; beta 2-adrenergic receptor; NEDD4; ubiquitination
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Funding
- Milton Fund
- Harvard School of Public Health
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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.
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