Differential activity and selectivity of N-terminal modified CXCL12 chemokines at the CXCR4 and ACKR3 receptors

Jaracz‐Ros, Agnieszka; Bernadat, Guillaume; Cutolo, Pasquale; Gallego, Carmen; Gustavsson, Martin; Cecon, Erika; Baleux, Françoise; Kufareva, Irina; Handel, Tracy M.; Bachelerie, Françoise; Levoye, Angélique

doi:10.1002/jlb.2ma0320-383rr

Cited by 11 publications

(19 citation statements)

References 67 publications

(168 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We thus investigated which of these two mechanisms is defective in the context of resistance to CXCL12. To this end, we repeated infection assays of CD4TL with RES or SENS viruses in the presence of P2G, a CXCL12 variant that binds CXCR4 with comparable affinity compared to CXCL12 but does not internalize the receptor [43][44][45]. As previously shown [43], P2G had a reduced anti-HIV-1 potency compared to CXCL12 (S4 Fig), presumably due to lack of CXCR4 endocytosis [23].…”

Section: Cxcl12 Is Impaired In Its Ability To Block the Binding Of Res Viruses To Cxcr4mentioning

confidence: 85%

Mechanisms of HIV-1 evasion to the antiviral activity of chemokine CXCL12 indicate potential links with pathogenesis

et al. 2021

View full text Add to dashboard Cite

HIV-1 infects CD4 T lymphocytes (CD4TL) through binding the chemokine receptors CCR5 or CXCR4. CXCR4-using viruses are considered more pathogenic, linked to accelerated depletion of CD4TL and progression to AIDS. However, counterexamples to this paradigm are common, suggesting heterogeneity in the virulence of CXCR4-using viruses. Here, we investigated the role of the CXCR4 chemokine CXCL12 as a driving force behind virus virulence. In vitro, CXCL12 prevents HIV-1 from binding CXCR4 and entering CD4TL, but its role in HIV-1 transmission and propagation remains speculative. Through analysis of thirty envelope glycoproteins (Envs) from patients at different stages of infection, mostly treatment-naïve, we first interrogated whether sensitivity of viruses to inhibition by CXCL12 varies over time in infection. Results show that Envs resistant (RES) to CXCL12 are frequent in patients experiencing low CD4TL levels, most often late in infection, only rarely at the time of primary infection. Sensitivity assays to soluble CD4 or broadly neutralizing antibodies further showed that RES Envs adopt a more closed conformation with distinct antigenicity, compared to CXCL12-sensitive (SENS) Envs. At the level of the host cell, our results suggest that resistance is not due to improved fusion or binding to CD4, but owes to viruses using particular CXCR4 molecules weakly accessible to CXCL12. We finally asked whether the low CD4TL levels in patients are related to increased pathogenicity of RES viruses. Resistance actually provides viruses with an enhanced capacity to enter naive CD4TL when surrounded by CXCL12, which mirrors their situation in lymphoid organs, and to deplete bystander activated effector memory cells. Therefore, RES viruses seem more likely to deregulate CD4TL homeostasis. This work improves our understanding of the pathophysiology and the transmission of HIV-1 and suggests that RES viruses’ receptors could represent new therapeutic targets to help prevent CD4TL depletion in HIV+ patients on cART.

show abstract

Section: Cxcl12 Is Impaired In Its Ability To Block the Binding Of Res Viruses To Cxcr4mentioning

confidence: 85%

Mechanisms of HIV-1 evasion to the antiviral activity of chemokine CXCL12 indicate potential links with pathogenesis

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Binding of these receptors to chemokines can induce the quick internalization and degradation of these proteins ( 24 ). Accordingly, CXCL12 can interact with its alternative receptor, CXCR7, also known as ACKR3, or with heterodimers formed between CXCR4 and CXCR7 ( 10 , 25 , 26 ). After this interaction, CXCR7 induces intracellular signaling and stimulates the relocalization of β-arrestins, eventually leading to the internalization and degradation of CXCL12 ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

“…There are atypical chemokine receptors (ACKRs), which do not activate classic G protein-dependent signaling cascades ( 10 , 24 ). Binding of these receptors to chemokines can induce the quick internalization and degradation of these proteins ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

“…Chemokine CXCL12, also known as stromal cell-derived factor-1 (SDF-1), belongs to the group of chemokines without the Glu-Leu-Arg motif in their N terminus (ELR-negative) ( 9 ). This protein can interact with its main receptor (CXCR4) and with the atypical receptor (CXCR7) ( 10 ). By interacting with CXCR4, chemokine CXCL12 stimulates the migration of several cell types, including epithelial cells ( 11 ), fibroblasts ( 12 ), endothelial cells ( 13 ), and inflammatory cells ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Immunoexpression of CXCL12 and CXCR4 in sporadic and Gorlin-Goltz syndrome-related odontogenic keratocysts

Lima¹,

Andrade²,

Cavalcante³

et al. 2022

J Clin Exp Dent

View full text Add to dashboard Cite

Background Differences in the pathogenesis and biological behavior of sporadic and Gorlin-Goltz syndrome-related odontogenic keratocysts (OKCs) have been reported, but the underlying mechanisms are not fully elucidated. Chemokine CXCL12 and its main receptor CXCR4 regulate important events in the pathogenesis of several lesions. Material and Methods This study evaluated the immunoexpression of CXCL12 and CXCR4 in sporadic and syndromic OKCs. Twenty-two sporadic OKCs and 22 syndromic OKCs were subjected to immunohistochemistry. The percentages of cytoplasmic (CXCL12 and CXCR4) and nuclear (CXCR4) staining in epithelial and fibrous capsule cells were determined. The results were analyzed statistically using the nonparametric Mann-Whitney test and Spearman correlation test ( p <0.05). Results Higher cytoplasmic expression of CXCL12 was observed in the epithelial lining and fibrous capsule of sporadic OKCs compared to syndromic OKCs ( p <0.001). No statistically significant differences in the cytoplasmic expression of CXCR4 were observed between syndromic OKCs and sporadic OKCs ( p >0.05). Compared to syndromic OKCs, sporadic OKCs exhibited higher nuclear expression of CXCR4 in the epithelial lining and lower immunoexpression in the fibrous capsule ( p <0.05). In the epithelial lining of syndromic OKCs, positive correlation was observed between cytoplasmic and nuclear expressions of CXCR4 ( p =0.003). In the fibrous capsule of syndromic OKCs and sporadic OKCs, cytoplasmic and nuclear expressions of CXCR4 were positively correlated ( p <0.001). Conclusions The results suggest a potential participation of CXCL12 and CXCR4 in the development of OKCs. The heterogeneous expression of these proteins in syndromic and sporadic OKCs may reflect differences in their pathogenesis and biological behavior. Key words: Odontogenic keratocyst, CXCL12, CXCR4, Immunohistochemistry.

show abstract

“…Since the first two N-terminal positions of CXCL12 are critical for activation and even conservative mutations can lead to drastic signaling defects [22][23][24] , we focused our initial computational design on improving the binding of the sensor to positions 3 through 8 of the CXCL12-derived peptide (P3 through P8), up to the CXC motif. Our design strategy focuses on the first-shell of residues in contact with the peptide ligand, thus we expect to improve binding, however, we also inevitably reinforce previously identified 23,[25][26][27] or uncover new allosteric sites on the pocket surface.…”

mentioning

confidence: 99%

Computational design of dynamic receptor—peptide signaling complexes applied to chemotaxis

Roberts

Oggier

Fuglistaler

et al. 2022

Preprint

View full text Add to dashboard Cite

Engineering biosensors that sensitively recognize specific biomolecules and trigger functional cellular responses is a holy grail of diagnostics and synthetic cell biology. Biosensor design approaches have mostly focused on binding structurally well-defined molecules. Coupling the sensing of flexible compounds to complex cellular responses would considerably expand biosensor applications, but remains challenging. We developed a computational strategy for designing highly sensitive receptor biosensors of flexible peptides. Using the method, we created ultrasensitive chemotactic GPCR:peptide pairs capable of eliciting potent chemotaxis in human primary T cells. Through mutual induced fit, our flexible structure design approach enhanced peptide contacts with binding and allosteric sites in the ligand pocket to achieve unprecedented signaling efficacy and potency. The approach paves the road for designing peptide-sensing receptors and expanding the biosensor toolbox for basic and therapeutic applications.

show abstract

Differential activity and selectivity of N-terminal modified CXCL12 chemokines at the CXCR4 and ACKR3 receptors

Cited by 11 publications

References 67 publications

Mechanisms of HIV-1 evasion to the antiviral activity of chemokine CXCL12 indicate potential links with pathogenesis

Mechanisms of HIV-1 evasion to the antiviral activity of chemokine CXCL12 indicate potential links with pathogenesis

Immunoexpression of CXCL12 and CXCR4 in sporadic and Gorlin-Goltz syndrome-related odontogenic keratocysts

Computational design of dynamic receptor—peptide signaling complexes applied to chemotaxis

Contact Info

Product

Resources

About