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“Glyco-sulfo barcodes” regulate chemokine receptor function

Chemokine ligands and receptors regulate the directional migration of leukocytes. Post-translational modifications of chemokine receptors including O-glycosylation and tyrosine sulfation have been reported to regulate ligand binding and resulting signaling. Through in silico analyses, we determined...

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Detalles Bibliográficos
Autores principales: Verhallen, Lisa, Lackman, Jarkko J., Wendt, Rikke, Gustavsson, Martin, Yang, Zhang, Narimatsu, Yoshiki, Sørensen, Daniel M., Lafferty, Kato Mac, Gouwy, Mieke, Marques, Pedro E., Hjortø, Gertrud M., Rosenkilde, Mette M., Proost, Paul, Goth, Christoffer K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894980/
https://www.ncbi.nlm.nih.gov/pubmed/36729338
http://dx.doi.org/10.1007/s00018-023-04697-9
Descripción
Sumario:Chemokine ligands and receptors regulate the directional migration of leukocytes. Post-translational modifications of chemokine receptors including O-glycosylation and tyrosine sulfation have been reported to regulate ligand binding and resulting signaling. Through in silico analyses, we determined potential conserved O-glycosylation and sulfation sites on human and murine CC chemokine receptors. Glyco-engineered CHO cell lines were used to measure the impact of O-glycosylation on CC chemokine receptor CCR5, while mutation of tyrosine residues and treatment with sodium chlorate were performed to determine the effect of tyrosine sulfation. Changing the glycosylation or tyrosine sulfation on CCR5 reduced the receptor signaling by the more positively charged CCL5 and CCL8 more profoundly compared to the less charged CCL3. The loss of negatively charged sialic acids resulted only in a minor effect on CCL3-induced signal transduction. The enzymes GalNAc-T1 and GalNAc-T11 were shown to be involved in the process of chemokine receptor O-glycosylation. These results indicate that O-glycosylation and tyrosine sulfation are involved in the fine-tuning and recognition of chemokine interactions with CCR5 and the resulting signaling. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-023-04697-9.