Identification of a Postendocytic Sorting Sequence in CCR5

Delhaye, Maurine; Gravot, Audrey; Ayinde, Diana; Niedergang, Florence; Alizon, Marc; Brelot, Anne

doi:10.1124/mol.107.038422

Cited by 35 publications

(29 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such a motif is present in the sequence of several GPCRs, and chemokine receptor CCR5 bears the sequence (EISVGL), whereas CXCR4, another chemokine receptor, does not (SFHSS). It was reported previously that CCR5 could interact with a PDZ-containing protein NHERF1 (31). Here, we present the first reported example of an interaction of any NHERF1 PDZ domain via a type two PDZ interacting domain.…”

Section: Discussionmentioning

confidence: 53%

Na+/H+ Exchanger Regulatory Factor-1 Is Involved in Chemokine Receptor Homodimer CCR5 Internalization and Signal Transduction but Does Not Affect CXCR4 Homodimer or CXCR4-CCR5 Heterodimer

Hammad

Kuang

Yan

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Chemokine receptors are members of the G protein-coupled receptor (GPCR) family. CCR5 is also the principal co-receptor for macrophage-tropic strains of human immunodeficiency virus, type 1 (HIV-1), and efforts have been made to develop ligands to inhibit HIV-1 infection by promoting CCR5 receptor endocytosis. Given the nature of GPCRs and their propensity to form oligomers, one can consider ligand-based therapies as unselective in terms of the oligomeric composition of complexes. For example, a ligand targeting a CCR5 homomer could likely induce signal transduction on a heteromeric CCR5-CXCR4. Other avenues could therefore be explored. We identified a receptor adaptor interacting specifically with one receptor complex but not others. NHERF1, an adaptor known for its role in desensitization, internalization, and regulation of the ERK signaling cascade for several GPCRs, interacts via its PDZ2 domain with the CCR5 homodimer but not with the CXCR4-CCR5 heterodimer or CXCR4 homodimer. To further characterize this interaction, we also show that NHERF1 increases the CCR5 recruitment of arrestin2 following stimulation. NHERF1 is also involved in CCR5 internalization, as we demonstrate that coexpression of constructs bearing the PDZ2 domain can block CCR5 internalization. We also show that NHERF1 potentiates RANTES (regulated on activation normal T cell expressed and secreted)-induced ERK1/2 phosphorylation via CCR5 activation and that this activation requires NHERF1 but not arrestin2. Taken together, our results suggest that oligomeric receptor complexes can associate specifically with partners and that in this case NHERF1 could represent an interesting new target for the regulation of CCR5 internalization and potentially HIV infection.

show abstract

Section: Discussionmentioning

confidence: 53%

Na+/H+ Exchanger Regulatory Factor-1 Is Involved in Chemokine Receptor Homodimer CCR5 Internalization and Signal Transduction but Does Not Affect CXCR4 Homodimer or CXCR4-CCR5 Heterodimer

Hammad

Kuang

Yan

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…1). C termini have emerged as a crucial region of GPCRs governing various aspects of their function, such as expression (35,36), dimerization (37), signaling (36, 38 -40), trafficking (35,36,41), and binding to regula- (25) that funnels G i -selective receptors to the G q pathway. Cells were treated with increasing agonist concentrations for 45 min and assayed for total IP accumulation, as described in detail under "Experimental Procedures."…”

Section: The C-terminal Tail Of Crth2 Is Important For Cell Surfacementioning

confidence: 99%

The C-terminal Tail of CRTH2 Is a Key Molecular Determinant That Constrains Gαi and Downstream Signaling Cascade Activation

Schröder

Merten

Mathiesen

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Prostaglandin D 2 activation of the seven-transmembrane receptor CRTH2 regulates numerous cell functions that are important in inflammatory diseases, such as asthma. Despite its disease implication, no studies to date aimed at identifying receptor domains governing signaling and surface expression of human CRTH2. We tested the hypothesis that CRTH2 may take advantage of its C-tail to silence its own signaling and that this mechanism may explain the poor functional responses observed with CRTH2 in heterologous expression systems. Although the C terminus is a critical determinant for retention of CRTH2 at the plasma membrane, the presence of this domain confers a signaling-compromised conformation onto the receptor. Indeed, a mutant receptor lacking the major portion of its C-terminal tail displays paradoxically enhanced G␣ i and ERK1/2 activation despite enhanced constitutive and agonist-mediated internalization. Enhanced activation of G␣ i proteins and downstream signaling cascades is probably due to the inability of the tail-truncated receptor to recruit ␤-arrestin2 and undergo homologous desensitization. Unexpectedly, CRTH2 is not phosphorylated upon agonist-stimulation, a primary mechanism by which GPCR activity is regulated. Dynamic mass redistribution assays, which allow label-free monitoring of all major G protein pathways in real time, confirm that the C terminus inhibits G␣ i signaling of CRTH2 but does not encode G protein specificity determinants. We propose that intrinsic CRTH2 inhibition by its C terminus may represent a rather unappreciated strategy employed by a GPCR to specify the extent of G protein activation and that this mechanism may compensate for the absence of the classical phosphorylation-dependent signal attenuation.2 is a lipid mediator that has been considered essential in the development of inflammatory diseases such as asthma and atopic dermatitis (1-3). It is the major cyclooxygenase metabolite synthesized in allergen-activated mast cells and is released upon their immunological activation (4). The biological effects of PGD 2 are mediated by two G protein-coupled receptors, DP1 and DP2/CRTH2 (chemoattractant receptor homologous molecule expressed on T helper type 2 cells), respectively (5, 6). DP1 activation leads to G␣ s -mediated elevation of intracellular cyclic AMP, whereas activation of CRTH2 results in an increase in intracellular Ca 2ϩ levels via the G␣ i pathway and a decrease in cAMP, but also G protein-independent, arrestin-mediated cellular responses have been observed (5-7).CRTH2 in particular is expressed on eosinophils, basophils, and T helper type 2 lymphocytes. Activation by PGD 2 or its active metabolites transduces the chemokinetic activity on these immune cells and, by doing so, mediates their recruitment to sites of inflammation (2, 3, 6, 8 -13). In mouse models of allergic asthma or atopic dermatitis, CRTH2 activation promotes eosinophilia and exacerbates pathology (14 -17). In humans, the proinflammatory role of CRTH2 is underscored by the finding that sequence...

show abstract

“…To assess these hypotheses, we compared the abilities of PSC-RANTES and CCL4 to down-regulate WT-CCR5 or the 349-CCR5 mutant, which does not recycle back to the cell surface (28) (Fig. 5D).…”

Section: Chemokine-mediated Inhibition Of Hiv Infection and Ccr5 Endomentioning

confidence: 99%

HIV-1 exploits CCR5 conformational heterogeneity to escape inhibition by chemokines

Colin

Benureau

Staropoli

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

CC chemokine receptor 5 (CCR5) is a receptor for chemokines and the coreceptor for R5 HIV-1 entry into CD4(+) T lymphocytes. Chemokines exert anti-HIV-1 activity in vitro, both by displacing the viral envelope glycoprotein gp120 from binding to CCR5 and by promoting CCR5 endocytosis, suggesting that they play a protective role in HIV infection. However, we showed here that different CCR5 conformations at the cell surface are differentially engaged by chemokines and gp120, making chemokines weaker inhibitors of HIV infection than would be expected from their binding affinity constants for CCR5. These distinct CCR5 conformations rely on CCR5 coupling to nucleotide-free G proteins ((NF)G proteins). Whereas native CCR5 chemokines bind with subnanomolar affinity to (NF)G protein-coupled CCR5, gp120/HIV-1 does not discriminate between (NF)G protein-coupled and uncoupled CCR5. Interestingly, the antiviral activity of chemokines is G protein independent, suggesting that "low-chemokine affinity" (NF)G protein-uncoupled conformations of CCR5 represent a portal for viral entry. Furthermore, chemokines are weak inducers of CCR5 endocytosis, as is revealed by EC50 values for chemokine-mediated endocytosis reflecting their low-affinity constant value for (NF)G protein-uncoupled CCR5. Abolishing CCR5 interaction with (NF)G proteins eliminates high-affinity binding of CCR5 chemokines but preserves receptor endocytosis, indicating that chemokines preferentially endocytose low-affinity receptors. Finally, we evidenced that chemokine analogs achieve highly potent HIV-1 inhibition due to high-affinity interactions with internalizing and/or gp120-binding receptors. These data are consistent with HIV-1 evading chemokine inhibition by exploiting CCR5 conformational heterogeneity, shed light into the inhibitory mechanisms of anti-HIV-1 chemokine analogs, and provide insights for the development of unique anti-HIV molecules

show abstract

Identification of a Postendocytic Sorting Sequence in CCR5

Cited by 35 publications

References 44 publications

Na+/H+ Exchanger Regulatory Factor-1 Is Involved in Chemokine Receptor Homodimer CCR5 Internalization and Signal Transduction but Does Not Affect CXCR4 Homodimer or CXCR4-CCR5 Heterodimer

Na+/H+ Exchanger Regulatory Factor-1 Is Involved in Chemokine Receptor Homodimer CCR5 Internalization and Signal Transduction but Does Not Affect CXCR4 Homodimer or CXCR4-CCR5 Heterodimer

The C-terminal Tail of CRTH2 Is a Key Molecular Determinant That Constrains Gαi and Downstream Signaling Cascade Activation

HIV-1 exploits CCR5 conformational heterogeneity to escape inhibition by chemokines

Contact Info

Product

Resources

About