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EMBO Rep. 2010 Aug;11(8):605-11. doi: 10.1038/embor.2010.80. Epub 2010 Jun 18.

Arrestin domain-containing protein 3 recruits the NEDD4 E3 ligase to mediate ubiquitination of the beta2-adrenergic receptor.

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  • 1Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

Abstract

Prolonged stimulation of the beta2-adrenergic receptor (beta2AR) 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 beta2AR 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 beta2AR. Knockdown of ARRDC3 expression abolishes the association between NEDD4 and beta2AR. 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 beta2AR ubiquitination.

PMID:
20559325
[PubMed - indexed for MEDLINE]
PMCID:
PMC2920442
Free PMC Article

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