Mechanisms regulating chemokine receptor activity

Abstract

Co-ordinated movement and controlled positioning of leucocytes is key to the development, maintenance and proper functioning of the immune system. Chemokines and their receptors play an essential role in these events by mediating directed cell migration, often referred to as chemotaxis. The chemotactic property of these molecules is also thought to contribute to an array of pathologies where inappropriate recruitment of specific chemokine receptor-expressing leucocytes is observed, including cancer and inflammatory diseases. As a result, chemokine receptors have become major targets for therapeutic intervention, and during the past 15 years much research has been devoted to understanding the regulation of their biological activity. From these studies, processes which govern the availability of functional chemokine receptors at the cell surface have emerged as playing a central role. In this review, we summarize and discuss current knowledge on the molecular mechanisms contributing to the regulation of chemokine receptor surface expression, from gene transcription and protein degradation to post-translational modifications, multimerization, intracellular transport and cross-talk.

Figure 1

Agonist-dependent (a) and independent (b, heterologous) chemokine receptor desensitization. (a) Following agonist binding and G protein mediated signalling, the chemokine receptor cytoplasmic tail is rapidly phosphorylated, usually by a G protein receptor kinase (GRK); this uncouples the G protein, which dissociates into guanosine triphosphate (GTP)-bound Gα and the Gβγ complex, and enables interaction with a β-arrestin, which acts as a scaffold targeting the receptor for internalization. Once internalized, the receptor follows recycling or degradation pathways. (b) Receptor X mediates cross-phosphorylation of the chemokine receptor, which may involve protein kinase C (PKC), leading to inhibition of chemokine-induced signalling and in some cases internalization of the receptor.

Figure 2

Intracellular transport of β-arrestin-bound CCR5 receptors following CCL5-treatment. Isolated human blood monocytes were treated with 100 nm CCL5 for the indicated time-period. Cells were fixed and permeabilized before labelling for CCR5 (red) and β-arrestins (green), as described previously. Scale bar 5 μm.

Figure 3

Different trafficking routes proposed for agonist-treated CCR5. Following agonist-stimulation, internalized CCR5 receptors are transported through the early endocytic pathway towards recycling and avoiding degradation. However, there are suggestions that the route followed by CCR5 may be ligand-dependent, as summarized here for the chemokine CCL5 and three of its derivatives.