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Ubiquitination regulates proteolytic processing of G protein-coupled receptors after their sorting to lysosomes.

Ubiquitination is essential for the endocytic sorting of various G protein-coupled receptors to lysosomes. Here we identify a distinct function of this covalent modification in controlling the later proteolytic processing of receptors. Mutation of all cytoplasmic lysine residues in the murine delta-opioid receptor blocked receptor ubiquitination without preventing ligand-induced endocytosis of receptors or their subsequent delivery to lysosomes, as verified by proteolysis of extramembrane epitope tags and down-regulation of radioligand binding to the transmembrane helices. Surprisingly, a functional screen revealed that the E3 ubiquitin ligase AIP4 specifically controls down-regulation of wild type receptors measured by radioligand binding without detectably affecting receptor delivery to lysosomes defined both immunochemically and biochemically. This specific AIP4-dependent regulation required direct ubiquitination of receptors and was also regulated by two deubiquitinating enzymes, AMSH and UBPY, which localized to late endosome/lysosome membranes containing internalized delta-opioid receptor. These results identify a distinct function of AIP4-dependent ubiquitination in controlling the later proteolytic processing of G protein-coupled receptors, without detectably affecting their endocytic sorting to lysosomes. We propose that ubiquitination or ubiquitination/deubiquitination cycling specifically regulates later proteolytic processing events required for destruction of the receptor's hydrophobic core.

Pubmed ID: 19433584


  • Hislop JN
  • Henry AG
  • Marchese A
  • von Zastrow M


The Journal of biological chemistry

Publication Data

July 17, 2009

Associated Grants

  • Agency: NIDA NIH HHS, Id: DA010711
  • Agency: NIDA NIH HHS, Id: DA012864
  • Agency: NIDA NIH HHS, Id: R01 DA026040
  • Agency: NIGMS NIH HHS, Id: R01 GM075159
  • Agency: NIGMS NIH HHS, Id: R01 GM075159-04

Mesh Terms

  • Binding, Competitive
  • Biotinylation
  • Cell Line
  • Electrophoresis, Polyacrylamide Gel
  • Endosomes
  • Green Fluorescent Proteins
  • Humans
  • Immunoblotting
  • Lysosomes
  • Microscopy, Fluorescence
  • Models, Biological
  • Mutation
  • Protein Processing, Post-Translational
  • Protein Transport
  • Radioligand Assay
  • Receptors, G-Protein-Coupled
  • Recombinant Fusion Proteins
  • Transfection
  • Ubiquitin
  • Ubiquitin-Protein Ligases
  • Ubiquitination