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Sci. Signal., 30 April 2013
Vol. 6, Issue 273, p. ra30
[DOI: 10.1126/scisignal.2003627]

RESEARCH ARTICLES

β-Arrestin–Dependent Activation of the Cofilin Pathway Is Required for the Scavenging Activity of the Atypical Chemokine Receptor D6

Elena M. Borroni1,2, Cinzia Cancellieri1,2, Alessandro Vacchini1,2, Yann Benureau3, Bernard Lagane3, Françoise Bachelerie4, Fernando Arenzana-Seisdedos3, Kensaku Mizuno5, Alberto Mantovani1,2, Raffaella Bonecchi1,2*, and Massimo Locati1,2

1 Department of Medical Biotechnologies and Translational Medicine, University of Milan, 20089 Rozzano, Milan, Italy.
2 Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy.
3 INSERM U819/Unité de Pathogénie Virale, Institut Pasteur, 75724 Paris, France.
4 INSERM UMRS996, University of Paris-Sud, Laboratory of Excellence in Research on Medication and Innovative Therapeutics (LERMIT), 92140 Clamart, France.
5 Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, 980-8578 Sendai, Miyagi, Japan.

Abstract: Chemokines promote the recruitment of leukocytes to sites of infection and inflammation by activating conventional heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs). Chemokines are also recognized by a set of atypical chemokine receptors (ACRs), which cannot induce directional cell migration but are required for the generation of chemokine gradients in tissues. ACRs are presently considered "silent receptors" because no G protein–dependent signaling activity is observed after their engagement by cognate ligands. We report that engagement of the ACR D6 by its ligands activates a β-arrestin1–dependent, G protein–independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin through the Rac1–p21-activated kinase 1 (PAK1)–LIM kinase 1 (LIMK1) cascade. This signaling pathway is required for the increased abundance of D6 protein at the cell surface and for its chemokine-scavenging activity. We conclude that D6 is a signaling receptor that exerts its regulatory function on chemokine-mediated responses in inflammation and immunity through a distinct signaling pathway.

* Corresponding author. E-mail: raffaella.bonecchi{at}humanitasresearch.it

Citation: E. M. Borroni, C. Cancellieri, A. Vacchini, Y. Benureau, B. Lagane, F. Bachelerie, F. Arenzana-Seisdedos, K. Mizuno, A. Mantovani, R. Bonecchi, M. Locati, β-Arrestin–Dependent Activation of the Cofilin Pathway Is Required for the Scavenging Activity of the Atypical Chemokine Receptor D6. Sci. Signal. 6, ra30 (2013).

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