Agonist-promoted Ubiquitination of the G Protein-coupled Receptor CXCR4 Mediates Lysosomal Sorting Export

@article{citeulike:2870430, abstract = {Ligand-induced trafficking plays an important role in the physiologic regulation of many G protein-coupled receptors (GPCRs). Although numerous GPCRs are sorted to a degradative pathway upon prolonged stimulation, the molecular events leading to degradation are poorly understood. Here we report that the human immunodeficiency virus co-receptor CXCR4 undergoes rapid agonist-promoted degradation by a process involving endocytosis via clathrin-coated pits and subsequent sorting to lysosomes. Studies analyzing the sorting of various CXCR4 mutants revealed the presence of a degradation motif (SSLKILSKGK) in the carboxyl terminus of CXCR4. The first two serines as well as the dileucine motif were critical for agonist-induced endocytosis, whereas all three serines but not the dileucine were important in mediating degradation. Mutation of the three lysine residues had no effect on CXCR4 endocytosis yet completely inhibited receptor degradation. Because lysine residues represent potential sites of ubiquitination, we also examined the ubiquitination of CXCR4. Interestingly, CXCR4 was shown to undergo rapid agonist-promoted ubiquitination that was attenuated by mutation of the lysine residues within the degradation motif. These studies implicate a specific role for ubiquitination in sorting endocytosed GPCRs to lysosomes. 10.1074/jbc.C100527200}, author = {Marchese, Adriano and Benovic, Jeffrey L.}, citeulike-article-id = {2870430}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.C100527200}, citeulike-linkout-1 = {http://www.jbc.org/cgi/content/abstract/276/49/45509}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/11641392}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=11641392}, day = {30}, doi = {10.1074/jbc.C100527200}, journal = {J. Biol. Chem.}, keywords = {cxcr4, lysosomal, sorting, ubiquitination}, month = {November}, number = {49}, pages = {45509--45512}, posted-at = {2008-09-10 14:55:31}, priority = {2}, title = {Agonist-promoted Ubiquitination of the G Protein-coupled Receptor CXCR4 Mediates Lysosomal Sorting}, url = {http://dx.doi.org/10.1074/jbc.C100527200}, volume = {276}, year = {2001} }

TY - JOUR ID - citeulike:2870430 L3 - citeulike-article-id:2870430 N2 - Ligand-induced trafficking plays an important role in the physiologic regulation of many G protein-coupled receptors (GPCRs). Although numerous GPCRs are sorted to a degradative pathway upon prolonged stimulation, the molecular events leading to degradation are poorly understood. Here we report that the human immunodeficiency virus co-receptor CXCR4 undergoes rapid agonist-promoted degradation by a process involving endocytosis via clathrin-coated pits and subsequent sorting to lysosomes. Studies analyzing the sorting of various CXCR4 mutants revealed the presence of a degradation motif (SSLKILSKGK) in the carboxyl terminus of CXCR4. The first two serines as well as the dileucine motif were critical for agonist-induced endocytosis, whereas all three serines but not the dileucine were important in mediating degradation. Mutation of the three lysine residues had no effect on CXCR4 endocytosis yet completely inhibited receptor degradation. Because lysine residues represent potential sites of ubiquitination, we also examined the ubiquitination of CXCR4. Interestingly, CXCR4 was shown to undergo rapid agonist-promoted ubiquitination that was attenuated by mutation of the lysine residues within the degradation motif. These studies implicate a specific role for ubiquitination in sorting endocytosed GPCRs to lysosomes. 10.1074/jbc.C100527200 IS - 49 JF - J. Biol. Chem. EP - 45512 TI - Agonist-promoted Ubiquitination of the G Protein-coupled Receptor CXCR4 Mediates Lysosomal Sorting VL - 276 SP - 45509 KW - cxcr4 KW - lysosomal KW - sorting KW - ubiquitination AU - Marchese, Adriano AU - Benovic, Jeffrey PY - 2001/11/30/ UR - http://dx.doi.org/10.1074/jbc.C100527200 ER -