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Single-molecule imaging reveals distinct effects of ligands on CCR5 dynamics depending on its dimerization status

Fanny Momboisse, Giacomo Nardi, Philippe Colin, Melany Hery, Nelia Cordeiro, View ORCID ProfileOlivier Schwartz, Nathalie Sauvonnet, Fernando Arenzana-Seisdedos, View ORCID ProfileThibault Lagache, View ORCID ProfileBernard Lagane, Jean-Christophe Olivo-Marin, View ORCID ProfileAnne Brelot
doi: https://doi.org/10.1101/2021.12.20.473455
Fanny Momboisse
1Institut Pasteur, Université de Paris, CNRS UMR3569, Virus and Immunity Unit, F-75015 Paris, France
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Giacomo Nardi
2Institut Pasteur, Université de Paris, CNRS UMR 3691, BioImage Analysis Unit, F-75015 Paris, France
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Philippe Colin
3Infinity, Université de Toulouse, CNRS, INSERM, UPS, 31024 Toulouse Cedex 03, France
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Melany Hery
1Institut Pasteur, Université de Paris, CNRS UMR3569, Virus and Immunity Unit, F-75015 Paris, France
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Nelia Cordeiro
1Institut Pasteur, Université de Paris, CNRS UMR3569, Virus and Immunity Unit, F-75015 Paris, France
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Olivier Schwartz
1Institut Pasteur, Université de Paris, CNRS UMR3569, Virus and Immunity Unit, F-75015 Paris, France
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  • ORCID record for Olivier Schwartz
Nathalie Sauvonnet
5Institut Pasteur, Université de Paris, Group Intracellular Trafficking and Tissue Homeostasis, F-75015 Paris, France
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Fernando Arenzana-Seisdedos
4Institut Pasteur, Université de Paris, INSERM U1108, Viral Pathogenesis Unit, F-75015 Paris, France
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Thibault Lagache
2Institut Pasteur, Université de Paris, CNRS UMR 3691, BioImage Analysis Unit, F-75015 Paris, France
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  • For correspondence: anne.brelot@pasteur.fr thibault.lagache@pasteur.fr
Bernard Lagane
3Infinity, Université de Toulouse, CNRS, INSERM, UPS, 31024 Toulouse Cedex 03, France
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  • ORCID record for Bernard Lagane
Jean-Christophe Olivo-Marin
2Institut Pasteur, Université de Paris, CNRS UMR 3691, BioImage Analysis Unit, F-75015 Paris, France
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Anne Brelot
1Institut Pasteur, Université de Paris, CNRS UMR3569, Virus and Immunity Unit, F-75015 Paris, France
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  • For correspondence: anne.brelot@pasteur.fr thibault.lagache@pasteur.fr
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Abstract

G protein-coupled receptors (GPCR) are present at the cell surface in different conformational and oligomeric states. However, how these states impact GPCRs biological function and therapeutic targeting remains incompletely known. Here, we investigated this issue in living cells for the CC chemokine receptor 5 (CCR5), a major receptor in inflammation and the principal entry co-receptor for Human Immunodeficiency Viruses (HIV-1). We used TIRF microscopy and an original statistical method to track and classify the motion of different receptors subpopulations. We showed a diversity of ligand-free forms of CCR5 at the cell surface constituted of various oligomeric states and exhibiting transient Brownian and restricted motions. These forms were stabilized differently by distinct ligands. In particular, agonist stimulation restricted the mobility of CCR5 and led to its clustering, a feature depending on β-arrestin, while inverse agonist stimulation exhibited the opposite effect. These results suggest a link between receptor activation and immobilization. Applied to HIV-1 envelope glycoproteins gp120, our quantitative analysis revealed agonist-like properties of gp120s. Distinct gp120s influenced CCR5 dynamics differently, suggesting that they stabilize different CCR5 conformations. Then, using a dimerization-compromized mutant, we showed that dimerization (i) impacts CCR5 precoupling to G proteins, (ii) is a pre-requisite for the immobilization and clustering of receptors upon activation, and (iii) regulates receptor endocytosis, thereby impacting the fate of activated receptors. This study demonstrates that tracking the dynamic behavior of a GPCR is an efficient way to link GPCR conformations to their functions, therefore improving the development of drugs targeting specific receptor conformations.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Competing Interests: The authors declare that no competing interests exist.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 20, 2021.
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Single-molecule imaging reveals distinct effects of ligands on CCR5 dynamics depending on its dimerization status
Fanny Momboisse, Giacomo Nardi, Philippe Colin, Melany Hery, Nelia Cordeiro, Olivier Schwartz, Nathalie Sauvonnet, Fernando Arenzana-Seisdedos, Thibault Lagache, Bernard Lagane, Jean-Christophe Olivo-Marin, Anne Brelot
bioRxiv 2021.12.20.473455; doi: https://doi.org/10.1101/2021.12.20.473455
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Single-molecule imaging reveals distinct effects of ligands on CCR5 dynamics depending on its dimerization status
Fanny Momboisse, Giacomo Nardi, Philippe Colin, Melany Hery, Nelia Cordeiro, Olivier Schwartz, Nathalie Sauvonnet, Fernando Arenzana-Seisdedos, Thibault Lagache, Bernard Lagane, Jean-Christophe Olivo-Marin, Anne Brelot
bioRxiv 2021.12.20.473455; doi: https://doi.org/10.1101/2021.12.20.473455

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