Arrestin domain‐containing protein 3 recruits the NEDD4 E3 ligase to mediate ubiquitination of the β2‐adrenergic receptor |
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| Authors: | Joseph F Nabhan Hui Pan Quan Lu |
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| Affiliation: | 1. Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts, 02115 USA;2. Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts, 02115 USA |
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| Abstract: | Prolonged stimulation of the β2‐adrenergic receptor (β2AR) 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 β2AR 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 β2AR. Knockdown of ARRDC3 expression abolishes the association between NEDD4 and β2AR. 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 β2AR ubiquitination. |
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| Keywords: | ARRDC3 arrestin β 2‐adrenergic receptor NEDD4 ubiquitination |
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