Endocytic trafficking of chemokine receptors

Abstract

Chemokine receptors belong to the super family of G protein-coupled receptors (GPCRs). The cognate ligands for chemokine receptors are small circulating proteins known as chemokines. Upon binding to their cognate chemokines, receptors are rapidly desensitized, internalized onto early endosomes and sorted either into a recycling pathway or degradative pathway. Chemokine receptor trafficking is essential because it limits the magnitude and duration of signaling by removing receptors from the cell surface thereby limiting access to their ligands, but it also delivers bound chemokines to lysosomes for degradation. Receptor sorting into the recycling pathway contributes to resensitization of receptor signaling, whereas sorting into the degradative pathway leads to long-term attenuation of signaling. Recent studies have revealed some key information regarding the molecular determinants mediating chemokine receptor internalization and have shed light on the mechanisms dictating sorting into either the recycling or degradative pathways. Here I discuss our current understanding of the mechanisms mediating chemokine receptor trafficking with a focus primarily on recent findings for the chemokine receptor CXCR4.

Figure 1. Amino acid alignment of the carboxy-terminal tail of C-X-C chemokine receptors

Lysine residues highlighted in blue in the amino acid sequence of CXCR4 have been shown to be involved in ubiquitination and degradation of CXCR4 [21], whereas the lysine residues highlighted in CXCR2 [26] and CXCR3 [56] have been shown to not be involved in ubiquitination and degradation. The lysine residues highlighted in CXCR7 have been shown to be involved in ubiquitination and plasma membrane localization [46]. The serine residues highlighted in red in CXCR4 have been shown to be important for E3 ubiquitin ligase AIP4 binding and ubiquitination and degradation of CXCR4 [21,34]. The dileucine motif-like sequences highlighted in yellow have been shown to be important for agonist-induced internalization of CXCR2 [14] and CXCR4 [21]. The PDZ-like ligand in CXCR2 has been shown to be important for directing the receptor away from the degradative pathway [26]. Transmembrane domain 7 is indicated and the single letter amino acid code is used. The sequence for each receptor was obtained from GenBank under the following accession numbers: U11870 (CXCR1); U11869 (CXCR2); U32674 (CXCR3); AF005058 (CXCR4); X68829 (CXCR5); AF007545 (CXCR6); and BC008459 (CXCR7).

Figure 2. Trafficking patterns of the CXCL12 chemokine receptors CXCR4 and CXCR7

Upon binding to CXCL12, CXCR4 is ubiquitinated by the E3 ubiquitin ligase AIP4 at the plasma membrane. CXCR4 then internalizes to early endosomes and is sorted to lysosomes where it is degraded. Endosomal sorting of ubiquitinated CXCR4 is mediated by a complex and carefully regulated process that involves AIP4, β-arrestin-1, the ESCRT machinery and the AAA ATPase Vps4. In contrast, CXCR7 is constitutively ubiquitinated and upon binding CXCL12, is deubiquitinated and CXCL12 and CXCR7 co-internalize to early endosomes via a β-arrestin-1-dependent pathway. In the acidic environment of the endosome, CXCL12 dissociates from CXCR7 and while CXCR7 enters a Rab11-positive recycling compartment [57], CXCL12 is delivered to lysosomes for degradation. The ubiquitin moieties on CXCR4 target it into invaginating domains of early endosomes or multivesicular bodies, which pinch off and form the intraluminal vesicles. CXCR4 is found on the limiting membrane of multivesicular bodies and on the membranes of the intraluminal vesicles [58]. The multivesicular body fuses with lysosomes where degradation occurs.