Home LiteratureArticle Details
PMID: 19424180 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

The deubiquitinases USP33 and USP20 coordinate beta2 adrenergic receptor recycling and resensitization.

The EMBO journal ·Vol. 28 ·No. 12 ·2009-06-17 ·Pages 1684-96

Berthouze M, Venkataramanan V, Li Y, Shenoy SK

Abstract

Agonist-induced ubiquitination of the beta(2) adrenergic receptor (beta(2)AR) functions as an important post-translational modification to sort internalized receptors to the lysosomes for degradation. We now show that this ubiquitination is reversed by two deubiquitinating enzymes, ubiquitin-specific proteases (USPs) 20 and 33, thus, inhibiting lysosomal trafficking when concomitantly promoting receptor recycling from the late-endosomal compartments as well as resensitization of recycled receptors at the cell surface. Dissociation of constitutively bound endogenously expressed USPs 20 and 33 from the beta(2)AR immediately after agonist stimulation and reassociation on prolonged agonist treatment allows receptors to first become ubiquitinated and then deubiquitinated, thus, providing a 'trip switch' between degradative and recycling pathways at the late-endosomal compartments. Thus, USPs 20 and 33 serve as novel regulators that dictate both post-endocytic sorting as well as the intensity and extent of beta(2)AR signalling from the cell surface.

MeSH Terms
Adrenergic beta-2 Receptor Agonists Animals Arrestins/metabolism Catalytic Domain Cattle Cell Compartmentation Endocytosis Endosomes/enzymology Enzyme Activation Gene Knockdown Techniques Humans Lysosomes/enzymology Mutant Proteins/metabolism Protein Binding Protein Processing, Post-Translational Protein Transport Rats Receptors, Adrenergic, beta-2/metabolism Ubiquitin Thiolesterase/metabolism Ubiquitination beta-Arrestins
Chemicals
Adrenergic beta-2 Receptor Agonists Arrestins Mutant Proteins Receptors, Adrenergic, beta-2 USP20 protein, human beta-Arrestins USP33 protein, human Ubiquitin Thiolesterase
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Berthouze Magali
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Venkataramanan Vidya
Li Yi
Shenoy Sudha K
References (37)
37 references, click to expand
  1. Membrane trafficking of G protein-coupled receptors.
    Annu Rev Pharmacol Toxicol. 2004;44:559-609 PMID: 14744258
  2. Regulation of GPCRs by endocytic membrane trafficking and its potential implications.
    Annu Rev Pharmacol Toxicol. 2008;48:537-68 PMID: 18184106
  3. A genomic and functional inventory of deubiquitinating enzymes.
    Cell. 2005 Dec 2;123(5):773-86 PMID: 16325574
  4. Nedd4 mediates agonist-dependent ubiquitination, lysosomal targeting, and degradation of the beta2-adrenergic receptor.
    J Biol Chem. 2008 Aug 8;283(32):22166-76 PMID: 18544533
  5. The nature of the arrestin x receptor complex determines the ultimate fate of the internalized receptor.
    J Biol Chem. 2003 Mar 28;278(13):11623-32 PMID: 12525498
  6. Rapid recycling of beta-adrenergic receptors is dependent on the actin cytoskeleton and myosin Vb.
    Traffic. 2008 Nov;9(11):1958-71 PMID: 18785920
  7. Regulation of cardiac contractility by Rab4-modulated beta2-adrenergic receptor recycling.
    Proc Natl Acad Sci U S A. 2004 May 4;101(18):7082-7 PMID: 15105445
  8. ESCRTing proteins in the endocytic pathway.
    Trends Biochem Sci. 2007 Dec;32(12):561-73 PMID: 17988873
  9. Regulation of G protein-coupled receptor signaling by scaffold proteins.
    Circ Res. 2002 Oct 18;91(8):672-80 PMID: 12386143
  10. Solution conformation of Lys63-linked di-ubiquitin chain provides clues to functional diversity of polyubiquitin signaling.
    J Biol Chem. 2004 Feb 20;279(8):7055-63 PMID: 14645257
  11. Regulation of epidermal growth factor receptor down-regulation by UBPY-mediated deubiquitination at endosomes.
    Mol Biol Cell. 2005 Nov;16(11):5163-74 PMID: 16120644
  12. Seven-transmembrane receptors and ubiquitination.
    Circ Res. 2007 Apr 27;100(8):1142-54 PMID: 17463329
  13. Endocytosis: the DUB version.
    Trends Cell Biol. 2006 Nov;16(11):551-9 PMID: 16996268
  14. Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2.
    Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6650-5 PMID: 19363159
  15. Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling.
    Pharmacol Rev. 2001 Mar;53(1):1-24 PMID: 11171937
  16. G protein-coupled receptor sorting to endosomes and lysosomes.
    Annu Rev Pharmacol Toxicol. 2008;48:601-29 PMID: 17995450
  17. Deubiquitination of type 2 iodothyronine deiodinase by von Hippel-Lindau protein-interacting deubiquitinating enzymes regulates thyroid hormone activation.
    J Clin Invest. 2003 Jul;112(2):189-96 PMID: 12865408
  18. The ubiquitin-specific protease Usp4 regulates the cell surface level of the A2A receptor.
    Mol Pharmacol. 2006 Apr;69(4):1083-94 PMID: 16339847
  19. Regulation of receptor trafficking by GRKs and arrestins.
    Annu Rev Physiol. 2007;69:451-82 PMID: 17037978
  20. A deubiquitinating enzyme UBPY regulates the level of protein ubiquitination on endosomes.
    Traffic. 2006 Aug;7(8):1017-31 PMID: 16771824
  21. Trafficking patterns of beta-arrestin and G protein-coupled receptors determined by the kinetics of beta-arrestin deubiquitination.
    J Biol Chem. 2003 Apr 18;278(16):14498-506 PMID: 12574160
  22. beta2-adrenergic receptor signaling and desensitization elucidated by quantitative modeling of real time cAMP dynamics.
    J Biol Chem. 2008 Feb 1;283(5):2949-61 PMID: 18045878
  23. Ubiquitination of a novel deubiquitinating enzyme requires direct binding to von Hippel-Lindau tumor suppressor protein.
    J Biol Chem. 2002 Feb 15;277(7):4656-62 PMID: 11739384
  24. Seven-transmembrane-spanning receptors and heart function.
    Nature. 2002 Jan 10;415(6868):206-12 PMID: 11805844
  25. The G-protein-coupled receptor phosphatase: a protein phosphatase type 2A with a distinct subcellular distribution and substrate specificity.
    Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8343-7 PMID: 7667292
  26. Sequestration and recycling of beta 2-adrenergic receptors permit receptor resensitization.
    Mol Pharmacol. 1995 Apr;47(4):666-76 PMID: 7723728
  27. Resistance of the human beta1-adrenergic receptor to agonist-induced ubiquitination: a mechanism for impaired receptor degradation.
    J Biol Chem. 2004 Nov 5;279(45):46882-9 PMID: 15331590
  28. Role of clathrin-mediated endocytosis in agonist-induced down-regulation of the beta2-adrenergic receptor.
    J Biol Chem. 1998 Mar 20;273(12):6976-81 PMID: 9507004
  29. AMSH is an endosome-associated ubiquitin isopeptidase.
    J Cell Biol. 2004 Aug 16;166(4):487-92 PMID: 15314065
  30. Identification of a deubiquitinating enzyme subfamily as substrates of the von Hippel-Lindau tumor suppressor.
    Biochem Biophys Res Commun. 2002 Jun 14;294(3):700-9 PMID: 12056827
  31. Beta-arrestins and cell signaling.
    Annu Rev Physiol. 2007;69:483-510 PMID: 17305471
  32. Differential affinities of visual arrestin, beta arrestin1, and beta arrestin2 for G protein-coupled receptors delineate two major classes of receptors.
    J Biol Chem. 2000 Jun 2;275(22):17201-10 PMID: 10748214
  33. The evasive nature of drug efficacy: implications for drug discovery.
    Trends Pharmacol Sci. 2007 Aug;28(8):423-30 PMID: 17659355
  34. Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin.
    Science. 2001 Nov 9;294(5545):1307-13 PMID: 11588219
  35. VHL protein-interacting deubiquitinating enzyme 2 deubiquitinates and stabilizes HIF-1alpha.
    EMBO Rep. 2005 Apr;6(4):373-8 PMID: 15776016
  36. Degradation of endocytosed epidermal growth factor and virally ubiquitinated major histocompatibility complex class I is independent of mammalian ESCRTII.
    J Biol Chem. 2006 Feb 24;281(8):5094-105 PMID: 16371348
  37. Trafficking of G protein-coupled receptors.
    Circ Res. 2006 Sep 15;99(6):570-82 PMID: 16973913
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2009.128
Published
2009-06-17
Epub
2009-00-07
Pages
1684-96
Language
English
Region
England
NLM ID
8208664
PMCID
PMC2699358
Subset
IM
Grants
NHLBI NIH HHS · R01 HL080525 · United States
NHLBI NIH HHS · R01 HL080525-04 · United States
NHLBI NIH HHS · HL 080525 · United States
External Links
PubMed source DOI: 10.1038/emboj.2009.128 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2