Chemokine receptor CCR2 undergoes transportin1-dependent nuclear translocation.
Chemokines (CCs) are small chemoattractant cytokines involved in a wide variety of biological and pathological processes. Released by cells in the milieu, and extracellular matrix and activating signalling cascades upon binding to specific G protein-coupled receptors (GPCRs), they trigger many cellular events. In various pathologies, CCs are directly responsible for excessive recruitment of leukocytes to inflammatory sites and recent studies using chemokine receptor (CCR) antagonists permitted these molecules to reach the market for medical use. While interaction of CCs with their receptors has been extensively documented, downstream GPCR signalling cascades triggered by CC are less well understood. Given the pivotal role of chemokine receptor 2 (CCR2) in monocyte recruitment, activation and differentiation and its implication in several autoimmune-inflammatory pathologies, we searched for potential new CCR2-interacting proteins by engineering a modified CCR2 that we used as bait. Herein, we show the direct interaction of CCR2 with transportin1 (TRN1), which we demonstrate is followed by CCR2 receptor internalization. Further characterization of this novel interaction revealed that TRN1-binding to CCR2 increased upon time in agonist treated cells and promotes its nuclear translocation in a TRN1-dependent manner. Finally, we provide evidence that following translocation, the receptor localizes at the outer edge of the nuclear envelope where it is finally released from TRN1.
Favre
Nicolas
N
Pharmionic Systems Ltd., Sion, Switzerland.
Camps
Montserrat
M
Arod
Christian
C
Chabert
Christian
C
Rommel
Christian
C
Pasquali
Christian
C
D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000378:metabolism; D002633:Chemotaxis; D002853:Chromatography, Liquid; D000939:Epitopes; D006388:Hemagglutinins / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D025941:Protein Interaction Mapping; D040901:Proteomics; D034741:RNA, Small Interfering / Q000235:genetics; D054390:Receptors, CCR2 / Q000378:metabolism*; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry; D028961:beta Karyopherins / Q000819:agonists / Q000502:physiology*
C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D000939:Epitopes; D006388:Hemagglutinins; D034741:RNA, Small Interfering; D054390:Receptors, CCR2; C108121:TNPO1 protein, human; D028961:beta Karyopherins