The atypical chemokine receptor 3 interacts with Connexin 43 inhibiting astrocytic gap junctional intercellular communication

Amos Fumagalli; Joyce Heuninck; Anne Pizzoccaro; Enora Moutin; Joyce Koenen; Martial Séveno; Thierry Durroux; Marie Pierre Junier; Géraldine Schlecht-Louf; Francoise Bachelerie; Dagmar Schütz; Ralf Stumm; Martine J. Smit; Nathalie C. Guérineau; Séverine Chaumont-Dubel; Philippe Marin

doi:10.1038/s41467-020-18634-y

The atypical chemokine receptor 3 interacts with Connexin 43 inhibiting astrocytic gap junctional intercellular communication

Amos Fumagalli
, Joyce Heuninck
, Anne Pizzoccaro
, Enora Moutin
, Joyce Koenen
, Martial Séveno
, Thierry Durroux
, Marie Pierre Junier
, Géraldine Schlecht-Louf
, Francoise Bachelerie
, Dagmar Schütz
, Ralf Stumm
, Martine J. Smit
, Nathalie C. Guérineau
, Séverine Chaumont-Dubel
, Philippe Marin^*

^*Corresponding author for this work

AIMMS

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

The atypical chemokine receptor 3 (ACKR3) plays a pivotal role in directing the migration of various cellular populations and its over-expression in tumors promotes cell proliferation and invasiveness. The intracellular signaling pathways transducing ACKR3-dependent effects remain poorly characterized, an issue we addressed by identifying the interactome of ACKR3. Here, we report that recombinant ACKR3 expressed in HEK293T cells recruits the gap junction protein Connexin 43 (Cx43). Cx43 and ACKR3 are co-expressed in mouse brain astrocytes and human glioblastoma cells and form a complex in embryonic mouse brain. Functional in vitro studies show enhanced ACKR3 interaction with Cx43 upon ACKR3 agonist stimulation. Furthermore, ACKR3 activation promotes β-arrestin2- and dynamin-dependent Cx43 internalization to inhibit gap junctional intercellular communication in primary astrocytes. These results demonstrate a functional link between ACKR3 and gap junctions that might be of pathophysiological relevance.

Original language	English
Article number	4855
Pages (from-to)	1-14
Number of pages	14
Journal	Nature Communications
Volume	11
Issue number	1
Early online date	25 Sept 2020
DOIs	https://doi.org/10.1038/s41467-020-18634-y
Publication status	Published - 1 Dec 2020

Funding

The authors thank all our colleagues from the ONCORNET consortium for continuous scientific discussions and support, Prof. Joël Bockaert (IGF) for critical reading of the manuscript and Steeve Thirard (iExplore facility, RAM/Biocampus) for technical assistance with animals. Time-lapse recordings and imaging experiments were performed using facilities of the MRI platform of the Biocampus service unit. LC-MS/MS analyses were performed using the facilities of the Functional Proteomics Platform of the Bio-campus service unit. BRET and DERET experiments were performed using the facilities of the Arpege pharmacological screening platform (Biocampus). This research was funded by a European Union’s Horizon2020 MSCA Program [Grant agreement 641833 (ONCORNET)]. A.F., S.C.D., and P.M. are also supported by CNRS, INSERM, Uni-versité de Montpellier and Fondation pour la Recherche Médicale (FRM).

Funders	Funder number
European Union’s Horizon2020 MSCA
Horizon 2020 Framework Programme	641833
Institut national de la santé et de la recherche médicale
Fondation pour la Recherche Médicale
Centre National de la Recherche Scientifique
Université de Montpellier

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1038/s41467-020-18634-y

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Cite this

Fumagalli, A., Heuninck, J., Pizzoccaro, A., Moutin, E., Koenen, J., Séveno, M., Durroux, T., Junier, M. P., Schlecht-Louf, G., Bachelerie, F., Schütz, D., Stumm, R., Smit, M. J., Guérineau, N. C., Chaumont-Dubel, S., & Marin, P. (2020). The atypical chemokine receptor 3 interacts with Connexin 43 inhibiting astrocytic gap junctional intercellular communication. Nature Communications, 11(1), 1-14. Article 4855. https://doi.org/10.1038/s41467-020-18634-y

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abstract = "The atypical chemokine receptor 3 (ACKR3) plays a pivotal role in directing the migration of various cellular populations and its over-expression in tumors promotes cell proliferation and invasiveness. The intracellular signaling pathways transducing ACKR3-dependent effects remain poorly characterized, an issue we addressed by identifying the interactome of ACKR3. Here, we report that recombinant ACKR3 expressed in HEK293T cells recruits the gap junction protein Connexin 43 (Cx43). Cx43 and ACKR3 are co-expressed in mouse brain astrocytes and human glioblastoma cells and form a complex in embryonic mouse brain. Functional in vitro studies show enhanced ACKR3 interaction with Cx43 upon ACKR3 agonist stimulation. Furthermore, ACKR3 activation promotes β-arrestin2- and dynamin-dependent Cx43 internalization to inhibit gap junctional intercellular communication in primary astrocytes. These results demonstrate a functional link between ACKR3 and gap junctions that might be of pathophysiological relevance.",

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Fumagalli, A, Heuninck, J, Pizzoccaro, A, Moutin, E, Koenen, J, Séveno, M, Durroux, T, Junier, MP, Schlecht-Louf, G, Bachelerie, F, Schütz, D, Stumm, R, Smit, MJ, Guérineau, NC, Chaumont-Dubel, S & Marin, P 2020, 'The atypical chemokine receptor 3 interacts with Connexin 43 inhibiting astrocytic gap junctional intercellular communication', Nature Communications, vol. 11, no. 1, 4855, pp. 1-14. https://doi.org/10.1038/s41467-020-18634-y

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AU - Junier, Marie Pierre

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AU - Bachelerie, Francoise

AU - Schütz, Dagmar

AU - Stumm, Ralf

AU - Smit, Martine J.

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AU - Chaumont-Dubel, Séverine

AU - Marin, Philippe

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The atypical chemokine receptor 3 interacts with Connexin 43 inhibiting astrocytic gap junctional intercellular communication

Abstract

Funding

UN SDGs

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Persistent URL (handle)

Other files and links

Fingerprint

ONCORNET2.0: Horizon2020 ONCOgenic Receptor Network of Excellence and Training 2.0

Cite this

The atypical chemokine receptor 3 interacts with Connexin 43 inhibiting astrocytic gap junctional intercellular communication

Abstract

Funding

UN SDGs

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Projects

ONCORNET2.0: Horizon2020 ONCOgenic Receptor Network of Excellence and Training 2.0

Cite this