ArticleThe Journal of biological chemistry2011
Beta2-adrenergic receptor lysosomal trafficking is regulated by ubiquitination of lysyl residues in two distinct receptor domains.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 51 citations in OpenAlex.
- β-Adrenergic Receptor Trafficking, Degradation, and Cell Surface Expression Are Altered in Dermal Fibroblasts from Hypertrophic Scars.The Journal of investigative dermatology · 2018Trial
- Renoprotective effects of tubular glucagon receptor activation mediated by V-ATPase.Science advances · 2026Article
- Adrenoceptor Desensitization: Current Understanding of Mechanisms.Pharmacological reviews · 2024Review
- Nedd4-2 up-regulation is associated with ACE2 ubiquitination in hypertension.Cardiovascular research · 2023Article
- Function and dynamics of the intrinsically disordered carboxyl terminus of β2 adrenergic receptor.Nature communications · 2023Article
- Lighting up Nobel Prize-winning studies with protein intrinsic disorder.Cellular and molecular life sciences : CMLS · 2022Review
- Post-Translational Modifications of G Protein-Coupled Receptors Revealed by Proteomics and Structural Biology.Frontiers in chemistry · 2022Review
- Spatial bias in cAMP generation determines biological responses to PTH type 1 receptor activation.Science signaling · 2021Article
- Respiratory syncytial virus induces βScience signaling · 2021Article
- Post-Translational Modifications of G Protein-Coupled Receptors Control Cellular Signaling Dynamics in Space and Time.Pharmacological reviews · 2021Review
- Agonist-activated glucagon receptors are deubiquitinated at early endosomes by two distinct deubiquitinases to facilitate Rab4a-dependent recycling.The Journal of biological chemistry · 2020Article
- Analysis of βProceedings of the National Academy of Sciences of the United States of America · 2020Article
- Interferon Receptor Trafficking and Signaling: Journey to the Cross Roads.Frontiers in immunology · 2020Review
- The deubiquitinase ubiquitin-specific protease 20 is a positive modulator of myocardial βThe Journal of biological chemistry · 2019Article
- Endo-lysosomal sorting of G-protein-coupled receptors by ubiquitin: Diverse pathways for G-protein-coupled receptor destruction and beyond.Traffic (Copenhagen, Denmark) · 2019Review
- Revealing the architecture of protein complexes by an orthogonal approach combining HDXMS, CXMS, and disulfide trapping.Nature protocols · 2018Article
- Site-specific polyubiquitination differentially regulates parathyroid hormone receptor-initiated MAPK signaling and cell proliferation.The Journal of biological chemistry · 2018Article
- GPCR desensitization: Acute and prolonged phases.Cellular signalling · 2018Review
- Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of β-adrenergic receptor signaling.JCI insight · 2017Article
- Regulation of G Protein-Coupled Receptors by Ubiquitination.International journal of molecular sciences · 2017Review
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
Agonist stimulation of the β2-adrenergic receptors (β2ARs) leads to their ubiquitination and lysosomal degradation. Inhibition of lysosomal proteases results in the stabilization and retention of internalized full-length β2ARs in the lysosomes, whereas inhibition of proteasomal proteases stabilizes newly synthesized β2ARs in nonlysosomal compartments. Additionally, a lysine-less β2AR (0K-β2AR) that is deficient in ubiquitination and degradation is not sorted to lysosomes unlike the WT β2AR, which is sorted to lysosomes. Thus, lysosomes are the primary sites for the degradation of agonist-activated, ubiquitinated β2ARs. To identify the specific site(s) of ubiquitination required for lysosomal sorting of the β2AR, four mutants, with lysines only in one intracellular domain, namely, loop 1, loop 2, loop 3, and carboxyl tail were generated. All of these receptor mutants coupled to G proteins, recruited β-arrestin2, and internalized just as the WT β2AR. However, only loop 3 and carboxyl tail β2ARs with lysines in the third intracellular loop or in the carboxyl tail were ubiquitinated and sorted for lysosomal degradation. As a complementary approach, we performed MS-based proteomic analyses to directly identify ubiquitination sites within the β2AR. We overexpressed and purified the β2AR from HEK-293 cells with or without prior agonist exposure and subjected trypsin-cleaved β2AR to LC-MS/MS analyses. We identified ubiquitinated lysines in the third intracellular loop (Lys-263 and Lys-270) and in the carboxyl tail (Lys-348, Lys-372, and Lys-375) of the β2AR. These findings introduce a new concept that two distinct domains in the β2AR are involved in ubiquitination and lysosomal degradation, contrary to the generalization that such regulatory mechanisms occur mainly at the carboxyl tails of GPCRs and other transmembrane receptors.
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