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Sci. Signal., 7 July 2009
Vol. 2, Issue 78, p. ra33
[DOI: 10.1126/scisignal.2000444]
RESEARCH ARTICLES
Oxygen-Regulated β2-Adrenergic Receptor Hydroxylation by EGLN3 and Ubiquitylation by pVHL
Liang Xie1,
Kunhong Xiao1,
Erin J. Whalen1,
Michael T. Forrester2,
Robert S. Freeman3,
Guohua Fong4,
Steven P. Gygi5,
Robert J. Lefkowitz1,2,6, and
Jonathan S. Stamler1,2*
1 Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. 2 Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA. 3 Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14621, USA. 4 Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030, USA. 5 Department of Cell Biology, Harvard University Medical School, Boston, MA 02115, USA. 6 Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
Abstract:
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 β-arrestin and affiliated E3 ligases mediate agonist-stimulated lysosomal degradation of the β2-adrenergic receptor (β2AR), 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 β2AR, thereby decreasing receptor abundance. We further show that the interaction of pVHL with β2AR is dependent on proline hydroxylation (proline-382 and -395) and that the dioxygenase EGLN3 interacts directly with the β2AR to serve as an endogenous β2AR 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 β2AR 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.
* To whom correspondence should be addressed. E-mail: staml001{at}mc.duke.edu
Citation: L. Xie, K. Xiao, E. J. Whalen, M. T. Forrester, R. S. Freeman, G. Fong, S. P. Gygi, R. J. Lefkowitz, J. S. Stamler, Oxygen-Regulated β2-Adrenergic Receptor Hydroxylation by EGLN3 and Ubiquitylation by pVHL. Sci. Signal.2, ra33 (2009).
Regulation of Cellular Levels of Sprouty2 Protein by Prolyl Hydroxylase Domain and von Hippel-Lindau Proteins.
K. Anderson, K. A. Nordquist, X. Gao, K. C. Hicks, B. Zhai, S. P. Gygi, and T. B. Patel (2011)
J. Biol. Chem.
286, 42027-42036
|Abstract »|Full Text »|PDF »
Rescue of the mutant CFTR chloride channel by pharmacological correctors and low temperature analyzed by gene expression profiling.
E. Sondo, V. Tomati, E. Caci, A. I. Esposito, U. Pfeffer, N. Pedemonte, and L. J. V. Galietta (2011)
Am J Physiol Cell Physiol
301, C872-C885
|Abstract »|Full Text »|PDF »
Ascorbic acid regulates osterix expression in osteoblasts by activation of prolyl hydroxylase and ubiquitination-mediated proteosomal degradation pathway.
Deficiency of a Transmembrane Prolyl 4-Hydroxylase in the Zebrafish Leads to Basement Membrane Defects and Compromised Kidney Function.
J. Hyvarinen, M. Parikka, R. Sormunen, M. Ramet, K. Tryggvason, K. I. Kivirikko, J. Myllyharju, and P. Koivunen (2010)
J. Biol. Chem.
285, 42023-42032
|Abstract »|Full Text »|PDF »
International Union of Basic and Clinical Pharmacology. LXXX. The Class Frizzled Receptors.
{beta}2- but not {beta}1-adrenoceptor activation modulates intracellular oxygen availability.
J. Li, B. Yan, Z. Huo, Y. Liu, J. Xu, Y. Sun, Y. Liu, D. Liang, L. Peng, Y. Zhang, et al. (2010)
J. Physiol.
588, 2987-2998
|Abstract »|Full Text »|PDF »
