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Scientific article
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English

Arylsulfatases and neuraminidases modulate engagement of CCR5 by chemokines by removing key electrostatic interactions

Published inScientific reports, vol. 14, no. 1, 7399
Publication date2024-01-02
First online date2024-01-02
Abstract

The chemokine receptor CCR5 is known to exist in cell surface subpopulations that differ in their capacity to engage ligands. One proposed explanation for this phenomenon is the presence of CCR5 species with different levels of post-translational modifications (PTMs). Tyrosine sulfation and O-glycan sialylation are PTMs that add negative charges to the extracellular domain of CCR5 and make strong contributions to chemokine binding but it is not known whether cellular mechanisms to control their levels exist. In this study we used a combination of sulfation-sensitive and sulfation-insensitive CCR5 ligands to show that the rate of turnover of CCR5 tyrosine sulfation is more rapid than the rate of turnover of the receptor itself. This suggests that the steady state level of CCR5 sulfation is maintained through the combination of tyrosine protein sulfotransferase (TPST), the trans-Golgi network (TGN)-resident ‘source enzyme, and a ‘sink’ activity that removes tyrosine sulfation from CCR5. By measuring the effects on ligand binding of knockdown and overexpression experiments, we provided evidence that non-lysosomal cellular arylsulfatases, particularly ARSG, ARSI and ARSJ, are CCR5 sulfation ‘sink’ enzymes. We also used targeted knockdown and sialylation-sensitive and insensitive chemokines to identify the sialidase NEU3 as a candidate ‘sink’ enzyme for CCR5 O-glycan sialylation. This study provides the first experimental evidence of activity of sulfatase and sialidase ‘sink’ enzymes on CCR5, providing a potential mechanism for cells to control steady-state levels of these PTMs and thereby exert dynamic control over receptor-ligand interactions at the cell surface and during receptor desensitization.

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NotePublished erratum in : Pinheiro I, Calo N, Paolini-Bertrand M, Hartley O. Author Correction: Arylsulfatases and neuraminidases modulate engagement of CCR5 by chemokines by removing key electrostatic interactions. Sci Rep. 2024 Mar 28;14(1):7399. doi: 10.1038/s41598-024-57806-4.
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Citation (ISO format)
DE MAGALHAES PINHEIRO, Inês et al. Arylsulfatases and neuraminidases modulate engagement of CCR5 by chemokines by removing key electrostatic interactions. In: Scientific reports, 2024, vol. 14, n° 1, p. 7399. doi: 10.1038/s41598-023-50944-1
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ISSN of the journal2045-2322
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