Arrestin domain-containing protein 3 recruits the NEDD4 E3 ligase to mediate ubiquitination of the beta2-adrenergic receptor.
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.
Mesh Terms:
Amino Acid Sequence, Animals, Arrestins, Cell Line, Endosomal Sorting Complexes Required for Transport, Gene Knockdown Techniques, Humans, Molecular Sequence Data, RNA Interference, RNA, Small Interfering, Receptors, Adrenergic, beta-2, Recombinant Fusion Proteins, Sequence Alignment, Ubiquitin-Protein Ligases, Ubiquitination
Amino Acid Sequence, Animals, Arrestins, Cell Line, Endosomal Sorting Complexes Required for Transport, Gene Knockdown Techniques, Humans, Molecular Sequence Data, RNA Interference, RNA, Small Interfering, Receptors, Adrenergic, beta-2, Recombinant Fusion Proteins, Sequence Alignment, Ubiquitin-Protein Ligases, Ubiquitination
EMBO Rep.
Date: Aug. 01, 2010
PubMed ID: 20559325
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