The α-arrestin ARRDC3 mediates ALIX ubiquitination and G protein–coupled receptor lysosomal sorting

Dores, Michael R.; Lin, Huilan; Grimsey, Neil; Mendez, Francisco; Trejo, JoAnn

doi:10.1091/mbc.e15-05-0284

Cited by 78 publications

(96 citation statements)

References 38 publications

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“…1D). Although our studies suggest that ARRDC3 is primarily localized at EEA1-positive early endosomes in HEK293 and BT549 cells, it's worth noting that Dores et al (35) found that overexpressed ARRDC3 was equally distributed on both early and late endosomes in HeLa cells. Thus, it appears that the cellular localization of ARRDC3 is dependent on both the cell type and expression level.…”

Section: Discussioncontrasting

confidence: 64%

“…Although previous studies suggested that ARRDC3 localizes to both the plasma membrane and endocytic vesicles, these observations were made in heterologous cell lines overexpressing ARRDC3 (15,19,34,35). Using fixed-cell confocal immunofluorescence microscopy, we demonstrated that both overexpressed (Fig.…”

Section: Discussionmentioning

confidence: 64%

“…Finally, it will also be interesting to evaluate whether ARRDC3 regulates the degradation of GPCRs that normally undergo rapid degradation upon endocytosis. Although this remains to be investigated, a recent study demonstrated that ARRDC3 can regulate the lysosomal sorting of PAR1 via its ability to promote ubiquitination of ALIX, a protein that directly binds to some GPCRs to mediate lysosomal sorting (35). Thus, ARRDC3 may have a diverse role in regulating GPCR sorting.…”

Section: Discussionmentioning

confidence: 99%

“…These results support the conclusion that the high BRET ratio between the ␤ 2 AR-RlucII and GFP10-ARRDC3 is indeed a result of protein-protein interaction. To further support these results, we performed an in vitro pulldown assay using purified FLAG-tagged ␤ 2 AR in the presence or absence of ISO or propranolol along with in vitro translated 35 S-labeled ARRDC3. ARRDC3 was able to bind to the ␤ 2 AR, and this binding was unaffected by ligand (Fig.…”

Section: Arrdc3 Is Localized On Eea1-positive Early Endosomes Andmentioning

confidence: 95%

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The α-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the β2-Adrenergic Receptor

Tian

Irannejad

Bowman

et al. 2016

Journal of Biological Chemistry

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Arrestin domain-containing protein 3 (ARRDC3) is a member of the mammalian ␣-arrestin family, which is predicted to share similar tertiary structure with visual-/␤-arrestins and also contains C-terminal PPXY motifs that mediate interaction with E3 ubiquitin ligases. Recently, ARRDC3 has been proposed to play a role in regulating the trafficking of G protein-coupled receptors, although mechanistic insight into this process is lacking. Here, we focused on characterizing the role of ARRDC3 in regulating the trafficking of the ␤ 2 -adrenergic receptor (␤ 2 AR). We find that ARRDC3 primarily localizes to EEA1-positive early endosomes and directly interacts with the ␤ 2 AR in a ligand-independent manner. Although ARRDC3 has no effect on ␤ 2 AR endocytosis or degradation, it negatively regulates ␤ 2 AR entry into SNX27-occupied endosomal tubules. This results in delayed recycling of the receptor and a concomitant increase in ␤ 2 AR-dependent endosomal signaling. Thus, ARRDC3 functions as a switch to modulate the endosomal residence time and subsequent intracellular signaling of the ␤ 2 AR.

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Section: Discussioncontrasting

confidence: 64%

Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Arrdc3 Is Localized On Eea1-positive Early Endosomes Andmentioning

confidence: 95%

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The α-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the β2-Adrenergic Receptor

Tian

Irannejad

Bowman

et al. 2016

Journal of Biological Chemistry

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“…Upon PAR1 activation, ARRDC3 recruits HECT-type E3 ubiquitin ligase WWP2 which ubiquitinates ALIX. In this way, ARRDC3 facilitates the sorting of PAR1 into ILVs of MVBs [110]. The mechanisms that control ALIX-dependent GPCR sorting at the multivesicular endosomes remain poorly understood; however, it is speculated that ubiquitin may regulate ALIX by facilitating its dimerization, which in turn can promote its interaction with the ESCRT-III complex [110].…”

Section: Lysosomal Degradationmentioning

confidence: 99%

Regulation of G Protein-Coupled Receptors by Ubiquitination

Skieterska

Rondou

Craenenbroeck

2017

Preprint

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G protein-coupled receptors (GPCRs) comprise the largest family of membrane receptors that control many cellular processes and consequently often serve as drug targets. These receptors undergo a strict regulation by mechanisms such as internalization and desensitization, which are strongly influenced by posttranslational modifications. Ubiquitination is a posttranslational modification with a broad range of functions that is currently gaining increased appreciation as a regulator of GPCR activity. The role of ubiquitination in directing GPCRs for lysosomal degradation has already been well-established. Furthermore, this modification can also play a role in targeting membrane and endoplasmic reticulum-associated receptors to the proteasome. Most recently, ubiquitination was also shown to be involved in GPCR signaling. In this review, we present current knowledge on the molecular basis of GPCR regulation by ubiquitination, and highlight the importance of E3 ubiquitin ligases, deubiquitinating enzymes and β-arrestins. Finally, we discuss classical and newly-discovered functions of ubiquitination in controlling GPCR activity.

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Spatial Mechano‐Signaling Regulation of GTPases through Non‐Degradative Ubiquitination

Sewduth,

Carai,

Ivanisevic

et al. 2023

Advanced Science

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Blood flow produces shear stress exerted on the endothelial layer of the vessels. Spatial characterization of the endothelial proteome is required to uncover the mechanisms of endothelial activation by shear stress, as blood flow varies in the vasculature. An integrative ubiquitinome and proteome analysis of shear‐stressed endothelial cells demonstrated that the non‐degradative ubiquitination of several GTPases is regulated by mechano‐signaling. Spatial analysis reveals increased ubiquitination of the small GTPase RAP1 in the descending aorta, a region exposed to laminar shear stress. The ubiquitin ligase WWP2 is identified as a novel regulator of RAP1 ubiquitination during shear stress response. Non‐degradative ubiquitination fine‐tunes the function of GTPases by modifying their interacting network. Specifically, WWP2‐mediated RAP1 ubiquitination at lysine 31 switches the balance from the RAP1/ Talin 1 (TLN1) toward RAP1/ Afadin (AFDN) or RAP1/ RAS Interacting Protein 1 (RASIP1) complex formation, which is essential to suppress shear stress‐induced reactive oxygen species (ROS) production and maintain endothelial barrier integrity. Increased ROS production in endothelial cells in the descending aorta of endothelial‐specific Wwp2‐knockout mice leads to increased levels of oxidized lipids and inflammation. These results highlight the importance of the spatially regulated non‐degradative ubiquitination of GTPases in endothelial mechano‐activation.

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The α-arrestin ARRDC3 mediates ALIX ubiquitination and G protein–coupled receptor lysosomal sorting

Abstract: The novel ALIX-dependent GPCR sorting pathway is regulated by the a-arrestin ARRDC3. A critical role is also shown for the E3 ubiquitin ligase WWP2 in regulation of ALIX ubiquitination and lysosomal sorting of GPCRs.

Cited by 78 publications

References 38 publications

The α-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the β2-Adrenergic Receptor

The α-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the β2-Adrenergic Receptor

Regulation of G Protein-Coupled Receptors by Ubiquitination

Spatial Mechano‐Signaling Regulation of GTPases through Non‐Degradative Ubiquitination

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