Ligand-specific conformational transitions and intracellular transport are required for atypical chemokine receptor 3–mediated chemokine scavenging
| Autor: | Nikolaus Heveker, Nicolas Montpas, Véronique Pons, Gilles R.X. Hickson, Besma Benredjem, Geneviève St-Onge, David Rhainds, Mélanie Girard, Nassr Nama |
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| Rok vydání: | 2018 |
| Předmět: |
ACKR3
0301 basic medicine Receptor recycling CCR1 I-TAC Chemokine receptor ligand Biochemistry structure-function SDF-1 arrestin recruitment 03 medical and health sciences Chemokine receptor chemokine scavenging Membrane Biology Arrestin Humans CXCL11 atypical chemokine receptor Molecular Biology Receptors CXCR bioluminescence resonance energy transfer (BRET) Microscopy Confocal biology Chemistry chemokine receptor transport receptor recycling Cell Biology CXCL12 Flow Cytometry CXCR7 Chemokine CXCL12 Chemokine CXCL11 Cell biology HEK293 Cells 030104 developmental biology receptor endocytosis Mutation biology.protein CCL25 Protein Binding Signal Transduction CCL21 |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m117.814947 |
| Popis: | The atypical chemokine receptor ACKR3 contributes to chemotaxis by binding, internalizing, and degrading the chemokines CXCL11 and CXCL12 to shape and terminate chemotactic gradients during development and immune responses. Although unable to trigger G protein activation, both ligands activate G protein–independent ACKR3 responses and prompt arrestin recruitment. This offers a model to specifically study ligand-specific receptor conformations leading to G protein–independent signaling and to functional parameters such as receptor transport and chemokine degradation. We here show chemokine specificity in arrestin recruitment, by different effects of single amino acid substitutions in ACKR3 on arrestin in response to CXCL12 or CXCL11. Chemokine specificity in receptor transport was also observed, as CXCL11 induced faster receptor internalization, slower recycling, and longer intracellular sojourn of ACKR3 than CXCL12. Internalization and recycling rates of the ACKR3 R1423.50A substitution in response to each chemokine were similar; however, ACKR3 R1423.50A degraded only CXCL12 and not CXCL11. This suggests that ligand-specific intracellular receptor transport is required for chemokine degradation. Remarkably, the failure of ACKR3 R1423.50A to degrade CXCL11 was not caused by the lack of arrestin recruitment; rather, arrestin was entirely dispensable for scavenging of either chemokine. This suggests the involvement of another, yet unidentified, ACKR3 effector in scavenging. In summary, our study correlates ACKR3 ligand-specific conformational transitions with chemokine-dependent receptor transport dynamics and points toward unexpected ligand specificity in the mechanisms of chemokine degradation. |
| Databáze: | OpenAIRE |
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