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.
Highlights
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
As Connexin 43 (Cx43) activity is often regulated by the alteration of its trafficking[36], we investigated if ACKR3induced inhibition of gap junctional intercellular communication (GJIC) in primary cultured astrocytes is mediated by Cx43 internalization
ACKR3 was previously found to interact with the gap junction beta-2 protein GJB2, but not Cx43, in a large interactomic screen exploring the interactome of 1125 GFP-tagged proteins expressed in HeLa cells[42]
Summary
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. ACKR3 activation promotes β-arrestin2- and dynamin-dependent Cx43 internalization to inhibit gap junctional intercellular communication in primary astrocytes. ACKR3 is over-expressed in numerous cancer types[7], including glioma, where both its expression and activation have been positively correlated with increased proliferative state and invasiveness[8] Despite this accumulating knowledge, the intracellular pathways underlying ACKR3-dependent effects remain poorly characterized. Over the last two decades, it has become evident that 7-TM receptors interact with large networks of proteins that finely control their targeting to specific subcellular compartments, their trafficking in and out of the plasma membrane and the nature of receptor-operated signal transduction[15] In line with these findings, studies have shown that ACKR3 exerts its biological effects by interacting with diverse membrane receptors[16].
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