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Papers In Press, published online ahead of print October 24, 2002
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143
Corresponding Author: mbt2m{at}itsa.ucsf.edu
Ubiquitination of cytoplasmic lysine residues can target G protein-coupled receptors (GPCRs) to proteasomes and has recently been shown to also be required for sorting of certain GPCRs to lysosomes following ligand-induced endocytosis. We addressed the generality of this mechanism by examining regulated proteolysis of the murine delta opioid receptor (DOR) expressed in human embryonic kidney (HEK) 293 cells, a well characterized model system in which receptors are sorted to lysosomes following ligand-induced endocytosis. Incubation of cells in the presence of the highly specific proteasome inhibitor lactacystin did not detectably affect ligand-induced proteolysis of DOR but significantly delayed ligand-induced proteolysis of epidermal growth factor receptors. Mutation of all cytoplasmic lysine residues in DOR, creating a mutant opioid receptor that is unable to be ubiquitinated, did not detectably inhibit either ligand-induced endocytosis or proteolytic degradation of endocytosed receptors. Furthermore, the lysine-mutated DOR, like its wild type counterpart, colocalized extensively with LAMP1-containing lysosomes after ligand-induced endocytosis. These results demonstrate that ubiquitination of DOR is not required either for its ligand-induced endocytosis or for post-endocytic trafficking to lysosomes. To our knowledge the present study establishes the first example of a mammalian GPCR that is efficiently targeted to lysosomes in the absence of covalent ubiquitination.
J. Biol. Chem, 10.1074/jbc.C200536200
Submitted on September 20, 2002
Revised on October 21, 2002
Accepted on October 24, 2002
Ubiquitination-independent trafficking of G protein-coupled receptors to lysosomes
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