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MARCH2 promotes endocytosis and lysosomal sorting of carvedilol-bound β(2)-adrenergic receptors.

Publication ,  Journal Article
Han, S-O; Xiao, K; Kim, J; Wu, J-H; Wisler, JW; Nakamura, N; Freedman, NJ; Shenoy, SK
Published in: J Cell Biol
November 26, 2012

Lysosomal degradation of ubiquitinated β(2)-adrenergic receptors (β(2)ARs) serves as a major mechanism of long-term desensitization in response to prolonged agonist stimulation. Surprisingly, the βAR antagonist carvedilol also induced ubiquitination and lysosomal trafficking of both endogenously expressed β(2)ARs in vascular smooth muscle cells (VSMCs) and overexpressed Flag-β(2)ARs in HEK-293 cells. Carvedilol prevented β(2)AR recycling, blocked recruitment of Nedd4 E3 ligase, and promoted the dissociation of the deubiquitinases USP20 and USP33. Using proteomics approaches (liquid chromatography-tandem mass spectrometry), we identified that the E3 ligase MARCH2 interacted with carvedilol-bound β(2)AR. The association of MARCH2 with internalized β(2)ARs was stabilized by carvedilol and did not involve β-arrestin. Small interfering RNA-mediated down-regulation of MARCH2 ablated carvedilol-induced ubiquitination, endocytosis, and degradation of endogenous β(2)ARs in VSMCs. These findings strongly suggest that specific ligands recruit distinct E3 ligase machineries to activated cell surface receptors and direct their intracellular itinerary. In response to β blocker therapy with carvedilol, MARCH2 E3 ligase activity regulates cell surface β(2)AR expression and, consequently, its signaling.

Duke Scholars

Published In

J Cell Biol

DOI

EISSN

1540-8140

Publication Date

November 26, 2012

Volume

199

Issue

5

Start / End Page

817 / 830

Location

United States

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Receptors, Adrenergic, beta-2
  • Rats
  • Propanolamines
  • Muscle, Smooth, Vascular
  • Mice
  • Membrane Proteins
  • Lysosomes
  • Humans
  • HEK293 Cells
 

Citation

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Han, S.-O., Xiao, K., Kim, J., Wu, J.-H., Wisler, J. W., Nakamura, N., … Shenoy, S. K. (2012). MARCH2 promotes endocytosis and lysosomal sorting of carvedilol-bound β(2)-adrenergic receptors. J Cell Biol, 199(5), 817–830. https://doi.org/10.1083/jcb.201208192
Han, Sang-oh, Kunhong Xiao, Jihee Kim, Jiao-Hui Wu, James W. Wisler, Nobuhiro Nakamura, Neil J. Freedman, and Sudha K. Shenoy. “MARCH2 promotes endocytosis and lysosomal sorting of carvedilol-bound β(2)-adrenergic receptors.J Cell Biol 199, no. 5 (November 26, 2012): 817–30. https://doi.org/10.1083/jcb.201208192.
Han S-O, Xiao K, Kim J, Wu J-H, Wisler JW, Nakamura N, et al. MARCH2 promotes endocytosis and lysosomal sorting of carvedilol-bound β(2)-adrenergic receptors. J Cell Biol. 2012 Nov 26;199(5):817–30.
Han, Sang-oh, et al. “MARCH2 promotes endocytosis and lysosomal sorting of carvedilol-bound β(2)-adrenergic receptors.J Cell Biol, vol. 199, no. 5, Nov. 2012, pp. 817–30. Pubmed, doi:10.1083/jcb.201208192.
Han S-O, Xiao K, Kim J, Wu J-H, Wisler JW, Nakamura N, Freedman NJ, Shenoy SK. MARCH2 promotes endocytosis and lysosomal sorting of carvedilol-bound β(2)-adrenergic receptors. J Cell Biol. 2012 Nov 26;199(5):817–830.

Published In

J Cell Biol

DOI

EISSN

1540-8140

Publication Date

November 26, 2012

Volume

199

Issue

5

Start / End Page

817 / 830

Location

United States

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Receptors, Adrenergic, beta-2
  • Rats
  • Propanolamines
  • Muscle, Smooth, Vascular
  • Mice
  • Membrane Proteins
  • Lysosomes
  • Humans
  • HEK293 Cells