Arrestin domain‐containing protein 3 recruits the NEDD4 E3 ligase to mediate ubiquitination of the β2‐adrenergic receptor

Nabhan, Joseph F.; Pan, Hui; Lu, Quan

doi:10.1038/embor.2010.80

Cited by 139 publications

(189 citation statements)

References 23 publications

(38 reference statements)

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“…To find highly conserved residues that might be important for the localization of ARRDC1 to the plasma membrane, we aligned amino acid sequences of human arrestin paralogs with ARRDC1 and with another ARRDC protein, ARRDC3, which also is known to localize to plasma membrane (Fig. 4B, Upper) (39,40). Several conserved residues (F88, G180, and N191) in the arrestin domain of ARRDC1 were identified.…”

Section: Resultsmentioning

confidence: 99%

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Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein

Nabhan¹,

Hu²,

Oh³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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552

534

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Mammalian cells are capable of delivering multiple types of membrane capsules extracellularly. The limiting membrane of late endosomes can fuse with the plasma membrane, leading to the extracellular release of multivesicular bodies (MVBs), initially contained within the endosomes, as exosomes. Budding viruses exploit the TSG101 protein and endosomal sorting complex required for transport (ESCRT) machinery used for MVB formation to mediate the egress of viral particles from host cells. Here we report the discovery of a virus-independent cellular process that generates microvesicles that are distinct from exosomes and which, like budding viruses, are produced by direct plasma membrane budding. Such budding is driven by a specific interaction of TSG101 with a tetrapeptide PSAP motif of an accessory protein, arrestin domain-containing protein 1 (ARRDC1), which we show is localized to the plasma membrane through its arrestin domain. This interaction results in relocation of TSG101 from endosomes to the plasma membrane and mediates the release of microvesicles that contain TSG101, ARRDC1, and other cellular proteins. Unlike exosomes, which are derived from MVBs, ARRDC1-mediated microvesicles (ARMMs) lack known late endosomal markers. ARMMs formation requires VPS4 ATPase and is enhanced by the E3 ligase WWP2, which interacts with and ubiquitinates ARRDC1. ARRDC1 protein discharged into ARMMs was observed in co-cultured cells, suggesting a role for ARMMs in intercellular communication. Our findings reveal an intrinsic cellular mechanism that results in direct budding of microvesicles from the plasma membrane, providing a formal paradigm for the evolutionary recruitment of ESCRT proteins in the release of budding viruses.Gag | receptor | ubiquitin | vesicle

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Section: Resultsmentioning

confidence: 99%

“…It remains unclear whether WWP1 also has a role in ARMMs production. Interestingly, our previous study showed that the ARRDC1 relative ARRDC3 also interacts with members of the NEDD4 E3 ligase family (40). Through interaction with NEDD4 E3 ligases, ARRDC3 mediates ubiquitination of β2-adrenergic receptors.…”

Section: Discussionmentioning

confidence: 99%

Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein

Nabhan¹,

Hu²,

Oh³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

552

534

View full text Add to dashboard Cite

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“…In reconstitution assays, Mdm2 was shown to ubiquitinate the ␤ 2 AR, and ␤-arrestin2 was required for this event (5). Additional studies have also implicated NEDD4 as an E3 ligase for the ␤ 2 AR, and NEDD4 has been shown to interact with the receptor in a ␤-arrestin-dependent (47) and ␤-arrestin-independent manner (49). Although these varying results may be due to differences in the assay design, they may also suggest that multiple E3 ligases may be able to ubiquitinate the same receptor.…”

Section: Discussionmentioning

confidence: 99%

Agonist-directed Interactions with Specific β-Arrestins Determine μ-Opioid Receptor Trafficking, Ubiquitination, and Dephosphorylation

Groer

Schmid

Jaeger

et al. 2011

Journal of Biological Chemistry

113

112

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Morphine and other opiates mediate their effects through activation of the -opioid receptor (MOR), and regulation of the MOR has been shown to critically affect receptor responsiveness. Activation of the MOR results in receptor phosphorylation, ␤-arrestin recruitment, and internalization. This classical regulatory process can differ, depending on the ligand occupying the receptor. There are two forms of ␤-arrestin, ␤-arrestin1 and ␤-arrestin2 (also known as arrestin2 and arrestin3, respectively); however, most studies have focused on the consequences of recruiting ␤-arrestin2 specifically. In this study, we examine the different contributions of ␤-arrestin1-and ␤-arrestin2-mediated regulation of the MOR by comparing MOR agonists in cells that lack expression of individual or both ␤-arrestins. Here we show that morphine only recruits ␤-arrestin2, whereas the MOR-selective enkephalin [D-Ala 2 ,N-MePhe 4 ,Gly 5 -ol]enkephalin (DAMGO), recruits either ␤-arrestin. We show that ␤-arrestins are required for receptor internalization and that only ␤-arrestin2 can rescue morphine-induced MOR internalization, whereas either ␤-arrestin can rescue DAMGO-induced MOR internalization. DAMGO activation of the receptor promotes MOR ubiquitination over time. Interestingly, ␤-arrestin1 proves to be critical for MOR ubiquitination as modification does not occur in the absence of ␤-arrestin1 nor when morphine occupies the receptor. Moreover, the selective interactions between the MOR and ␤-arrestin1 facilitate receptor dephosphorylation, which may play a role in the resensitization of the MOR and thereby contribute to overall development of opioid tolerance.Morphine and other opiates are among the most clinically useful analgesics, and their actions are mediated largely through activation of -opioid receptors (MORs).3 As a G protein-coupled receptor (GPCR), the MOR is subject to regulation paradigms that include phosphorylation by GPCR kinases (GRKs) and subsequent interactions with ␤-arrestins (␤-arrestin1, also known as arrestin2, and ␤-arrestin2, also known as arrestin3). ␤-Arrestins can then initiate receptor internalization, which in turn can promote both receptor down-regulation and resensitization (1-3). ␤-Arrestins can also facilitate these regulatory events by scaffolding ubiquitination machinery, such as E3 ligases, to GPCRs, as has been shown for the ␤ 2 adrenergic receptor (␤ 2 AR), V2 vasopressin receptor, and the chemokine receptor (CXCR4) (4 -6), however this has not been demonstrated for the MOR. MOR regulation has been shown to be contingent upon the particular agonist acting at the receptor as morphine promotes different regulatory events than other opioid ligands, including the D-enkephalin analog, [D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]enkephalin (DAMGO), fentanyl, methadone, and etorphine, although all of these ligands are full agonists at the MOR with respect to G protein coupling (7). The difference between agonists was first recognized when Arden et al. (8) observed that although DAMGO promotes robust internalizatio...

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“…6) where the process of transporter ubiquitination begins. During the preparation of our manuscript, two studies reported the involvement of Arrdc3 in the ubiquitination and degradation (but not in internalization) of ␤2-adrenergic receptor and ␤4-integrin (55,56).…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C-dependent Ubiquitination and Clathrin-mediated Endocytosis of the Cationic Amino Acid Transporter CAT-1

Viña-Vilaseca

Bender-Sigel

Sorkina

et al. 2011

Journal of Biological Chemistry

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Cationic amino acid transporter 1 (CAT-1) is responsible for the bulk of the uptake of cationic amino acids in most mammalian cells. Activation of protein kinase C (PKC) leads to downregulation of the cell surface CAT-1. To examine the mechanisms of PKC-induced down-regulation of CAT-1, a functional mutant of CAT-1 (CAT-1-HA-GFP) was generated in which a hemagglutinin antigen (HA) epitope tag was introduced into the second extracellular loop and GFP was attached to the carboxyl terminus. CAT-1-HA-GFP was stably expressed in porcine aorthic endothelial and human epithelial kidney (HEK) 293 cells. Using the HA antibody internalization assay we have demonstrated that PKC-dependent endocytosis was strongly inhibited by siRNA depletion of clathrin heavy chain, indicating that CAT-1-HA-GFP internalization requires clathrin-coated pits. Internalized CAT-1-HA-GFP was accumulated in early, recycling, and late endosomes. PKC activation also resulted in ubiquitination of CAT-1. CAT-1 ubiquitination and endocytosis in phorbol ester-stimulated porcine aorthic endothelial and HEK293 cells were inhibited by siRNA knockdown of NEDD4-2 and NEDD4-1 E3 ubiquitin ligases, respectively. In contrast, ubiquitination and endocytosis of the dopamine transporter was dependent on NEDD4-2 in all cell types tested. Altogether, our data suggest that ubiquitination mediated by NEDD4-2 or NEDD4-1 leading to clathrin-mediated endocytosis is the common mode of regulation of various transporter proteins by PKC. Cationic amino acid transporter (CAT)-12 is a member of the SLC7 gene family of membrane transport proteins. The SLC7 family is divided into two groups, glycosylated (CAT) and nonglycosylated transporters (reviewed in Ref. 1). The latter associate with a glycosylated protein from the SLC3 family to form heteromeric amino acid transporters. There are four proven members in the CAT subfamily: CAT-1, CAT-2A, CAT-2B, and CAT-3 (reviewed in Ref. 2). All CATs have a predicted topology of 14 transmembrane domains with cytoplasmic amino and carboxyl termini. The largest, third extracellular loop is glycosylated in all CATs. CAT-2 proteins are also glycosylated in the second loop. CAT-1 is expressed ubiquitously in all adult tissues except the liver (reviewed in Ref.3). The transport properties of CAT-1 resemble those of system y ϩ , defined by the selectivity for cationic amino acids, K m of 0.1-0.2 mM, Na ϩ and pH independence, and strong trans-stimulation. CAT-1 is ubiquitously expressed and the main portal of entry for cationic amino acids into mammalian cells. Homozygous knockout of CAT-1 in mice is postnatally lethal (4). CAT-1 activity has been reported to be regulated through activation of protein kinase C (PKC) (5, 6). Even though there are some discrepancies, most studies conclude that activation of PKC leads to inhibition of L-Arg uptake due to the decreased activity of CAT-1. Studies of CAT-1 phosphorylation and mutations of the PKC phosphorylation consensus sites in CAT-1 suggested that CAT-1 inhibition by PKC is not due to CAT-1 phosp...

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Arrestin domain‐containing protein 3 recruits the NEDD4 E3 ligase to mediate ubiquitination of the β2‐adrenergic receptor

Cited by 139 publications

References 23 publications

Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein

Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein

Agonist-directed Interactions with Specific β-Arrestins Determine μ-Opioid Receptor Trafficking, Ubiquitination, and Dephosphorylation

Protein Kinase C-dependent Ubiquitination and Clathrin-mediated Endocytosis of the Cationic Amino Acid Transporter CAT-1

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