Ubiquitylation of the chemokine receptor CCR7 enables efficient receptor recycling and cell migration.
The chemokine receptor CCR7 is essential for lymphocyte and dendritic cell homing to secondary lymphoid organs. Owing to the ability to induce directional migration, CCR7 and its ligands CCL19 and CCL21 are pivotal for the regulation of the immune system. Here, we identify a novel function for receptor ubiquitylation in the regulation of the trafficking process of this G-protein-coupled seven transmembrane receptor. We discovered that CCR7 is ubiquitylated in a constitutive, ligand-independent manner and that receptor ubiquitylation regulates the basal trafficking of CCR7 in the absence of chemokine. Upon CCL19 binding, we show that internalized CCR7 recycles back to the plasma membrane via the trans-Golgi network. An ubiquitylation-deficient CCR7 mutant internalized normally after ligand binding, but inefficiently recycled in immune cells and was transiently retarded in the trans-Golgi network compartment of HEK293 transfectants. Finally, we demonstrate that the lack of CCR7 ubiquitylation profoundly impairs immune cell migration. Our results provide evidence for a novel function of receptor ubiquitylation in the regulation of CCR7 recycling and immune cell migration.
Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Unterseestrasse 47, CH-8280 Kreuzlingen,  Switzerland.
Karin
K
Schaeuble
Mark A
MA
Hauser
Alexandra V
AV
Rippl
Roland
R
Bruderer
Carolina
C
Otero
Marcus
M
Groettrup
Daniel F
DF
Legler
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D018925:Chemokines / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D021382:Protein Sorting Signals; D021381:Protein Transport / Q000187:drug effects; D054400:Receptors, CCR7 / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D021601:trans-Golgi Network / Q000187:drug effects / Q000378:metabolism
C515370:CCR7 protein, human; D018925:Chemokines; D050505:Mutant Proteins; D021382:Protein Sorting Signals; D054400:Receptors, CCR7; D048049:Extracellular Signal-Regulated MAP Kinases; D008239:Lysine