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Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL.

Publication ,  Journal Article
Xie, L; Xiao, K; Whalen, EJ; Forrester, MT; Freeman, RS; Fong, G; Gygi, SP; Lefkowitz, RJ; Stamler, JS
Published in: Sci Signal
July 7, 2009

Agonist-induced ubiquitylation and degradation of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) play an essential role in surface receptor homeostasis, thereby tuning many physiological processes. Although beta-arrestin and affiliated E3 ligases mediate agonist-stimulated lysosomal degradation of the beta(2)-adrenergic receptor (beta(2)AR), a prototypic GPCR, the molecular cues that mark receptors for ubiquitylation and the regulation of receptor degradation by the proteasome remain poorly understood. We show that the von Hippel-Lindau tumor suppressor protein (pVHL)-E3 ligase complex, known for its regulation of hypoxia-inducible factor (HIF) proteins, interacts with and ubiquitylates the beta(2)AR, thereby decreasing receptor abundance. We further show that the interaction of pVHL with beta(2)AR is dependent on proline hydroxylation (proline-382 and -395) and that the dioxygenase EGLN3 interacts directly with the beta(2)AR to serve as an endogenous beta(2)AR prolyl hydroxylase. Under hypoxic conditions, receptor hydroxylation and subsequent ubiquitylation decrease dramatically, thus attenuating receptor degradation and down-regulation. Notably, in both cells and tissue, the abundance of endogenous beta(2)AR is shown to reflect constitutive turnover by EGLN3 and pVHL. Our findings provide insight into GPCR regulation, broaden the functional scope of prolyl hydroxylation, and expand our understanding of the cellular response to hypoxia.

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Published In

Sci Signal

DOI

EISSN

1937-9145

Publication Date

July 7, 2009

Volume

2

Issue

78

Start / End Page

ra33

Location

United States

Related Subject Headings

  • Von Hippel-Lindau Tumor Suppressor Protein
  • Ubiquitination
  • Receptors, Adrenergic, beta-2
  • Protein Binding
  • Proline
  • Procollagen-Proline Dioxygenase
  • Oxygen
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Hydroxylation
 

Citation

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Xie, L., Xiao, K., Whalen, E. J., Forrester, M. T., Freeman, R. S., Fong, G., … Stamler, J. S. (2009). Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL. Sci Signal, 2(78), ra33. https://doi.org/10.1126/scisignal.2000444
Xie, Liang, Kunhong Xiao, Erin J. Whalen, Michael T. Forrester, Robert S. Freeman, Guohua Fong, Steven P. Gygi, Robert J. Lefkowitz, and Jonathan S. Stamler. “Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL.Sci Signal 2, no. 78 (July 7, 2009): ra33. https://doi.org/10.1126/scisignal.2000444.
Xie L, Xiao K, Whalen EJ, Forrester MT, Freeman RS, Fong G, et al. Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL. Sci Signal. 2009 Jul 7;2(78):ra33.
Xie, Liang, et al. “Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL.Sci Signal, vol. 2, no. 78, July 2009, p. ra33. Pubmed, doi:10.1126/scisignal.2000444.
Xie L, Xiao K, Whalen EJ, Forrester MT, Freeman RS, Fong G, Gygi SP, Lefkowitz RJ, Stamler JS. Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL. Sci Signal. 2009 Jul 7;2(78):ra33.

Published In

Sci Signal

DOI

EISSN

1937-9145

Publication Date

July 7, 2009

Volume

2

Issue

78

Start / End Page

ra33

Location

United States

Related Subject Headings

  • Von Hippel-Lindau Tumor Suppressor Protein
  • Ubiquitination
  • Receptors, Adrenergic, beta-2
  • Protein Binding
  • Proline
  • Procollagen-Proline Dioxygenase
  • Oxygen
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Hydroxylation