1. The atypical chemokine receptor 3 interacts with Connexin 43 inhibiting astrocytic gap junctional intercellular communication.
- Author
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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, and Marin P
- Subjects
- Animals, Cell Proliferation, Connexin 43 drug effects, Connexins metabolism, Gene Knock-In Techniques, Glioblastoma metabolism, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein Interaction Domains and Motifs, Receptors, CXCR agonists, Receptors, CXCR genetics, Signal Transduction physiology, Astrocytes metabolism, Cell Communication physiology, Connexin 43 metabolism, Gap Junctions pathology, Receptors, CXCR metabolism
- 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.
- Published
- 2020
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