Chemokine receptor internalization and intracellular trafficking

doi:10.1016/j.cytogfr.2005.05.008

Cytokine & Growth Factor Reviews

Volume 16, Issue 6, December 2005, Pages 637-658

https://doi.org/10.1016/j.cytogfr.2005.05.008 Get rights and content

Abstract

The internalization and intracellular trafficking of chemokine receptors have important implications for the cellular responses elicited by chemokine receptors. The major pathway by which chemokine receptors internalize is the clathrin-mediated pathway, but some receptors may utilize lipid rafts/caveolae-dependent internalization routes. This review discusses the current knowledge and controversies regarding these two different routes of endocytosis. The functional consequences of internalization and the regulation of chemokine receptor recycling will also be addressed. Modifications of chemokine receptors, such as palmitoylation, ubiquitination, glycosylation, and sulfation, may also impact trafficking, chemotaxis and signaling. Finally, this review will cover the internalization and trafficking of viral and decoy chemokine receptors.

Introduction

Chemokine receptors undergo a basal level of internalization and degradation or recycling in the absence of ligand. Ligand binding can greatly enhance the internalization and trafficking of these G protein-coupled receptors (GPCRs) and can increase the dynamics of receptor sensitization versus desensitization and of receptor recycling versus degradation. The receptor trafficking pathways may vary depending on the presence or absence of ligand. Two major choices are available for this trafficking: clathrin-mediated endocytosis, versus lipid raft/caveolae-dependent internalization. Some receptors take advantage of both of these pathways, while others may follow one pathway the majority of the time. The cell type in which the receptor is expressed may in part determine the likelihood of utilization of one pathway as compared to another. This may be due to the ratio of specific adaptor proteins, the lipid composition of the membrane in proximity to the domain the receptor is localized in, or other poorly characterized determinates. The fate of the receptor after ligand stimulation (to traffic or not to traffic) may affect the length, strength, or type of intracellular signals generated. Moreover, the type of post-translational modifications of the receptor can also have major effects on ligand mediated signaling. In this review, we will cover four major aspects of chemokine receptor trafficking: clathrin mediated endocytosis; caveolae/lipid raft mediated trafficking; effects of receptor trafficking on downstream signal transduction and impact of receptor modifications on receptor trafficking and signaling.

Section snippets

Chemokine receptors and the clathrin-mediated endocytic pathway

A major mechanism by which chemokine receptors undergo ligand-induced internalization is through clathrin-mediated endocytosis (Fig. 1) [1], [2], [3], [4], [5]. The binding of ligand results in phosphorylation of Ser and Thr residues in the intracellular loops and carboxyl-terminus of the chemokine receptor by G protein-coupled receptor kinases (GRKs) (Table 1) [6], [7], [8], [9]. Phosphorylation results in the uncoupling of the G protein subunits from the receptor and receptor desensitization

Internalization of chemokine receptors via lipid rafts and caveolae

Recent studies suggest that the trafficking and signaling of certain chemokine receptors may, in some instances, be regulated by clathrin-independent pathways. These pathways may be mediated through lipid rafts or through cholesterol-rich structures called caveolae [26], [27], [28], [29].

Lipid rafts, also known as membrane rafts, glycosphingolipid-enriched microdomains, or detergent-resistant microdomains, are relatively resistant to solubilization with commonly used detergents such as

Regulation of chemokine receptor trafficking by Rab GTPases

Rabs are small GTPases that cycle between GDP-bound (inactive) and GTP-bound (active) states and regulate a number of cellular trafficking events. The exchange of GDP for GTP, GTP hydrolysis, and GDP displacement are regulated by guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), and GDP dissociation inhibitors (GDIs), respectively. Rabs are post-translationally modified with geranyl–geranyl groups at their carboxyl-termini [48], [49]. This modification allows Rabs

Regulation and functional consequences of internalization

The internalization of chemokine receptors occurs after ligand binds to the receptor. Depending on the percentage of receptors being activated, this process may dramatically reduce the level of membrane expression of the receptor and therefore change functionality. This ligand-triggered internalization is most likely the reason for the down regulation of most chemokine receptors, if not all of them. The rate of chemokine receptor internalization may be determined by several factors, such as the

Regulation of chemokine receptor recycling

Little is known about chemokine receptor recycling and what factors mediate the fate of the chemokine receptor once it is internalized. It is likely that many factors contribute to differential recycling of chemokine receptors (Table 3). These factors may include the duration and concentration of ligand stimulation as well as sorting motifs located in the intracellular domains of the receptor. It does appear that the length of stimulation with ligand plays a role in the recycling/degradation

Role of lipid rafts/caveloae in chemokine receptors functions

One of the most important functions for chemokine receptors is receptor-mediated chemotaxis. Lipid rafts/caveolae have been suggested to play a role in chemotaxis. This is based on the observation that oxidation of cholesterol or enriching the plasma membrane with 22-hydroxycholesterol results in inhibition of CCR5-mediated chemotaxis [106], [107], [108]. Moreover, inhibition of lipid raft formation prevents CXCL12-dependent migration [109]. Current evidence indicates that lipid rafts serve as

Modifications of chemokine receptors

Like other GPCRs, chemokine receptors can undergo various modifications (see Table 4). Facing either the intracellular world or the extracellular space, these molecular ornaments can determine the outlook of the mature receptors and hence drastically impact the physiological interactions with their partners and biological functions [113], [114]. The modifications located in the amino-terminal part or extracellular loops of the chemokine receptors, like Tyr sulfation and glycosylation, could be

Viral chemokine and decoy receptors

The human cytomegalovirus genome encodes four seven-transmembrane chemokine-like receptors: UL33, UL78, US28, and US27 [157], [158]. The function of these proteins is largely unknown. However, because these receptors can bind with high affinity to chemokines, it has been suggested that they may sequester chemokines in order for the virus to evade the immune response. The US28 receptor binds a number of CC-chemokines and the CX₃C chemokine fractalkine [159], [160], [161], [162]. It undergoes

Conclusions and perspectives

Chemokines and their receptors play an important role in a variety of biological processes, including host defense, inflammation, HIV infection, angiogenesis, and cancer metastasis. The involvement of chemokine receptors in disease makes them ideal candidates for therapeutic intervention. The elucidation of the mechanisms that regulate the cellular responses mediated by chemokines is crucial for the identification of therapeutic targets. An important aspect of chemokine receptor function is

Acknowledgements

This work was supported by grants from the NCI, CA34590 and T32 CA09592 and from the Department of Veterans Affairs, VA Merit (AR) and Career Scientist Award (AR), and a GRECC grant.

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¹: These authors contributed equally to this review.

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Chemokine receptor internalization and intracellular trafficking

Abstract

Introduction

Section snippets

Chemokine receptors and the clathrin-mediated endocytic pathway

Internalization of chemokine receptors via lipid rafts and caveolae

Regulation of chemokine receptor trafficking by Rab GTPases

Regulation and functional consequences of internalization

Regulation of chemokine receptor recycling

Role of lipid rafts/caveloae in chemokine receptors functions

Modifications of chemokine receptors

Viral chemokine and decoy receptors

Conclusions and perspectives

Acknowledgements

J Biol Chem

Life Sci

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Biochem Biophys Res Commun

J Biol Chem

Curr Opin Cell Biol

Semin Immunol

Trends Cell Biol

J Biol Chem

J Biol Chem

J Biol Chem

Blood

Exp Mol Pathol

J Biol Chem

J Biol Chem

J Biol Chem

J Mol Biol

Cell

Cell

Cell

Biochem Biophys Res Commun

Exp Cell Res

Blood

J Biol Chem

Curr Biol

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Cell

J Biol Chem

Blood

J Biol Chem

Biochem Biophys Res Commun

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Blood

J Allergy Clin Immunol

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Characterization of RANTES- and aminooxypentane-RANTES-triggered desensitization signals reveals differences in recruitment of the G protein-coupled receptor complex

J Immunol