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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.

Pubmed ID: 20559325


  • Nabhan JF
  • Pan H
  • Lu Q


EMBO reports

Publication Data

August 27, 2010

Associated Grants


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